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Aleksandra Galetin - One of the best experts on this subject based on the ideXlab platform.
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physiologically based pharmacokinetic modeling of Intestinal first pass metabolism of cyp3a substrates with high Intestinal extraction
Drug Metabolism and Disposition, 2011Co-Authors: Michael Gertz, Brian J Houston, Aleksandra GaletinAbstract:Prediction of Intestinal Availability (F(G)), in conjunction with hepatic metabolism, is of considerable importance in drug disposition to assess oral clearance and liability to drug-drug interactions. In the current study, F(G) predictions were performed within a physiologically based pharmacokinetic (PBPK) model using in vitro permeability and clearance data. The prediction success was assessed in comparison with the Q(Gut) model. In addition, apparent oral clearance values, predicted using the PBPK model, were compared with in vivo observations from meta-analyses. Finally, unbound intrinsic clearance values (CLu(int)) were determined for 12 CYP3A substrates in eight individual human jejunal microsome (HJM) samples to assess interindividual variability in Intestinal intrinsic clearance and subsequent F(G) predictions. Overall, the PBPK model improved F(G) predictions in comparison with the Q(Gut) model; this was apparent by a reduced bias and increased precision. In particular, F(G) predictions of indinavir, saquinavir, and terfenadine were model-dependent. The predicted oral clearance values of the drugs investigated ranged from 8.79 to 6320 l/h for tacrolimus and simvastatin, respectively, and were overall within 3-fold of the observed data with the exception of indinavir, atorvastatin, and buspirone. The individual HJM CLu(int) values ranged from 17 to 14,000 μl · min(-1) · mg(-1) for atorvastatin and saquinavir, respectively, and corresponding interindividual variability in CLu(int) estimates ranged from 41 to 67%. These in vitro data resulted in predicted F(G) values ranging from 0.03 to 0.94 for simvastatin and indinavir, respectively. The largest interindividual variability of F(G) was predicted for terfenadine (65%) in contrast with the low variability in the case of indinavir (3%).
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prediction of human drug clearance by multiple metabolic pathways integration of hepatic and Intestinal microsomal and cytosolic data
Drug Metabolism and Disposition, 2011Co-Authors: H Cubitt, Brian J Houston, Aleksandra GaletinAbstract:The current study assesses hepatic and Intestinal glucuronidation, sulfation, and cytochrome P450 (P450) metabolism of raloxifene, quercetin, salbutamol, and troglitazone using different in vitro systems. The fraction metabolized by conjugation and P450 metabolism was estimated in liver and intestine, and the importance of multiple metabolic pathways on accuracy of clearance prediction was assessed. In vitro intrinsic sulfation clearance (CLint, SULT) was determined in human Intestinal and hepatic cytosol and compared with hepatic and Intestinal microsomal glucuronidation (CLint, UGT) and P450 clearance (CLint, CYP) expressed per gram of tissue. Hepatic and Intestinal cytosolic scaling factors of 80.7 mg/g liver and 18 mg/g intestine were estimated from published data. Scaled CLint, SULT ranged between 0.7 and 11.4 ml · min−1 · g−1 liver and 0.1 and 3.3 ml · min−1 · g−1 intestine (salbutamol and quercetin were the extremes). Salbutamol was the only compound with a high extent of sulfation (51 and 28% of total CLint for liver and intestine, respectively) and also significant renal clearance (26–57% of observed plasma clearance). In contrast, the clearance of quercetin was largely accounted for by glucuronidation. Drugs metabolized by multiple pathways (raloxifene and troglitazone) demonstrated improved prediction of intravenous clearance using data from all hepatic pathways (44–86% of observed clearance) compared with predictions based only on the primary pathway (22–36%). The assumption of no Intestinal first pass resulted in underprediction of oral clearance for raloxifene, troglitazone, and quercetin (3–22% of observed, respectively). Accounting for the Intestinal contribution to oral clearance via estimated Intestinal Availability improved prediction accuracy for raloxifene and troglitazone (within 2.5-fold of observed). Current findings emphasize the importance of both hepatic and Intestinal conjugation for in vitro-in vivo extrapolation of metabolic clearance.
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prediction of human Intestinal first pass metabolism of 25 cyp3a substrates from in vitro clearance and permeability data
Drug Metabolism and Disposition, 2010Co-Authors: Michael Gertz, A Harrison, Brian J Houston, Aleksandra GaletinAbstract:Intestinal first-pass metabolism may contribute to low oral drug bioAvailability and drug-drug interactions, particularly for CYP3A substrates. The current analysis predicted Intestinal Availability (F(G)) from in vitro metabolic clearance and permeability data of 25 drugs using the Q(Gut) model. The drug selection included a wide range of physicochemical properties and in vivo F(G) values (0.07-0.94). In vitro clearance data (CLu(int)) were determined in human Intestinal (HIM) and three liver (HLM) microsomal pools (n = 105 donors) using the substrate depletion method. Apparent drug permeability (P(app)) was determined in Caco-2 and Madin-Darby canine kidney cells transfected with human MDR1 gene (MDCK-MDR1 cells) under isotonic conditions (pH = 7.4). In addition, effective permeability (P(eff)) data, estimated from regression analyses to P(app) or physicochemical properties were used in the F(G) predictions. Determined CLu(int) values ranged from 0.022 to 76.7 microl/min/pmol of CYP3A (zolpidem and nisoldipine, respectively). Differences in CLu(int) values obtained in HIM and HLM were not significant after normalization for tissue-specific CYP3A abundance, supporting their interchangeable usability. The F(G) predictions were most successful when P(app) data from Caco-2/MDCK-MDR1 cells were used directly; in contrast, the use of physicochemical parameters resulted in significant F(G) underpredictions. Good agreement between predicted and in vivo F(G) was noted for drugs with low to medium Intestinal extraction (e.g., midazolam predicted F(G) value 0.54 and in vivo value 0.51). In contrast, low prediction accuracy was observed for drugs with in vivo F(G) <0.5, resulting in considerable underprediction in some instances, as for saquinavir (predicted F(G) is 6% of the observed value). Implications of the findings are discussed.
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grapefruit juice drug interaction studies as a method to assess the extent of Intestinal Availability utility and limitations
Current Drug Metabolism, 2008Co-Authors: Michael Gertz, A Harrison, Brian J Houston, John D Davis, Aleksandra GaletinAbstract:This study aims to assess utility and limitations of grapefruit juice (GFJ) interaction studies as alternative in vivo approach to estimate Intestinal Availability (FG) in comparison to the predominantly used i.v./oral method. The FG estimates were obtained from the ratio of AUC in the control and the GFJ group reported previously. Due to large variability in the study design, the following inclusion criteria were applied for the selection of clinical studies: no change in elimination half-life in the presence of GFJ, administration of GFJ with or up to 4 h before drug intake, and a reported significant increase in AUC in the presence of GFJ. Weighted mean FG values were compared to estimates from i.v./oral data. Additionally, inter-study and inter-individual variation of GFJ FG estimates was assessed by meta-analysis for drugs with multiple studies reported. FG values ranged from 0.07 to 0.92 for lovastatin and quinidine, respectively. Overall, the inter-individual variation in GFJ FG estimates (16-54%) was higher than the inter-study (5.7-39%) with the exception of nisoldipine and simvastatin where inter-study variations of 53-88% were observed. Weighted average GFJ FG estimates were comparable to i.v./oral, supporting the application of this approach as an alternative to i.v./oral data for predominantly metabolised drugs (r2 = 0.65; n=10). In contrast, this approach is of limited use for drugs whose disposition is co-dependent on efflux/uptake transporters and metabolic enzymes. An area of high Intestinal extraction (FG0.25) is identified as problematic, as Availability of conclusive data is limited in this area.
Christopher J Gorski - One of the best experts on this subject based on the ideXlab platform.
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inhibition of human Intestinal wall metabolism by macrolide antibiotics effect of clarithromycin on cytochrome p450 3a4 5 activity and expression
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Amar Pinto, Dhanashri Kolwankar, Suthat Liangpunsakul, Million Arefayene, Christopher J Gorski, Mitchell A. Hamman, Naga Chalasani, Ying-hong Wang, Todd C. Skaar, Stephen D. HallAbstract:Background Clarithromycin increases both hepatic and Intestinal Availability of the selective cytochrome P450 (CYP) 3A probe midazolam. This study was designed to identify determinants of variability in the extent of Intestinal wall CYP3A inhibition by clarithromycin, such as CYP3A5 genotype, and the mechanism of inhibition. Methods Ten healthy volunteers received 500 mg oral clarithromycin twice a day for 7 days. Before and after administration of clarithromycin, small-bowel mucosal biopsy specimens were obtained endoscopically. Intestinal CYP3A activity was determined from the rate of 1′-hydroxymidazolam and 4-hydroxymidazolam formation by incubation of small-bowel homogenate with midazolam (25 Μmol/L) and NADPH for 5 minutes. Intestinal CYP3A4 and CYP3A5 messenger ribonucleic acid was quantified by real-time reverse transcriptase-polymerase chain reaction. Intestinal CYP3A4 and CYP3A5 protein concentrations were determined by immunoblotting. Serum and homogenate concentrations of midazolam, clarithromycin, and metabolites were determined by liquid chromatography-mass spectrometry. CYP3A5 genotype was determined by real-time polymerase chain reaction. Results The formation of 1′-hydroxymidazolam (1.36 ± 0.46 pmol · min−1 · mg−1 at baseline versus 0.35 ± 0.16 pmol · min−1 · mg−1 after administration) and 4-hydroxymidazolam (0.39 ± 0.12 pmol · min−1 · mg−1 at baseline versus 0.12 ± 0.05 pmol · min−1 · mg−1 after administration) was significantly (P < .001) reduced after clarithromycin administration. Clarithromycin administration did not result in a significant change in Intestinal CYP3A4 and CYP3A5 messenger ribonucleic acid and protein expression. All subjects had detectable serum clarithromycin concentrations after 7 days of clarithromycin (3.71 ± 2.43 Μmol/L). The mean concentration of clarithromycin in the Intestinal biopsy homogenate was 1.2 ± 0.7 nmol/L (range, 0.42–2.39 nmol/L). Compared with CYP3A5 nonexpressers, subjects with at least 1 CYP3A5*1 allele (CYP3A5 expressers) had greater inhibition of Intestinal CYP3A activity after treatment with clarithromycin. There was a strong linear relationship between the decrease in Intestinal CYP3A activity and baseline catalytic activity (R2 = 0.9). Conclusion Baseline Intestinal activity of CYP3A4 was a key determinant of variability of the inhibitory effect of clarithromycin among individuals. CYP3A5*1 alleles were associated with greater baseline Intestinal CYP3A activity and, therefore, greater extent of inhibition. The primary in vivo mechanism was not rapidly reversible competitive or irreversible inhibition but was likely formation of metabolic intermediate complexes. Clinical Pharmacology & Therapeutics (2005) 77, 178–188; doi: 10.1016/j.clpt.2004.10.002
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the effect of echinacea echinacea purpurea root on cytochrome p450 activity in vivo
Clinical Pharmacology & Therapeutics, 2004Co-Authors: Christopher J Gorski, Mitchell A. Hamman, J. Hilligoss, Shiew-mei Huang, Amar G. PintoAbstract:Background Echinacea is a widely available over-the-counter herbal remedy. Tinctures of echinacea have been shown to inhibit cytochrome P450 (CYP) in vitro. The effect of echinacea (Echinacea purpurea root) on CYP activity in vivo was assessed by use of the CYP probe drugs caffeine (CYP1A2), tolbutamide (CYP2C9), dextromethorphan (CYP2D6), and midazolam (hepatic and Intestinal CYP3A). Methods Twelve healthy subjects (6 men) completed this 2-period, open-label, fixed-schedule study. Caffeine, tolbutamide, dextromethorphan, and oral and intravenous midazolam were administered before and after a short course of echinacea (400 mg 4 times a day for 8 days) to determine in vivo CYP activities. Results Echinacea administration significantly increased the systemic clearance of midazolam by 34%, from 32 ± 7 L/h to 43 ± 16 L/h (P = .003; 90% confidence interval [CI], 116%-150%), and significantly reduced the midazolam area under the concentration-time curve by 23%, from 127 ± 36 μg · h/L to 102 ± 43 μg · h/L (P = .024; 90% CI, 63%-88%). In contrast, the oral clearance of midazolam was not significantly altered (P = .655; 90% CI, 75%-124%), 137 ± 19 L/h compared with 146 ± 71 L/h. The oral Availability of midazolam after echinacea dosing was significantly increased (P = .028; 90% CI, 108%-153%), from 0.23 ± 0.06 to 0.33 ± 0.13. Hepatic Availability (0.72 ± 0.08 versus 0.61 ± 0.16; P = .006; 90% CI, 73%-90%) and Intestinal Availability (0.33 ± 0.11 versus 0.61 ± 0.38; P = .015; 90% CI, 125%-203%) were significantly altered in opposite directions. Echinacea dosing significantly reduced the oral clearance of caffeine, from 6.6 ± 3.8 L/h to 4.9 ± 2.3 L/h (P = .049; 90% CI, 58%-96%). The oral clearance of tolbutamide was reduced by 11%, from 0.81 ± 0.18 L/h to 0.72 ± 0.19 L/h, but this change was not considered to be clinically relevant because the 90% CIs were within the 80% to 125% range. The oral clearance of dextromethorphan in 11 CYP2D6 extensive metabolizers was not affected by echinacea dosing (1289 ± 414 L/h compared with 1281 ± 483 L/h; P = .732; 90% CI, 89%-108%). Conclusions Echinacea (E purpurea root) reduced the oral clearance of substrates of CYP1A2 but not the oral clearance of substrates of CYP2C9 and CYP2D6. Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and Intestinal sites. The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and Intestinal sites. Caution should be used when echinacea is coadministered with drugs dependent on CYP3A or CYP1A2 for their elimination. Clinical Pharmacology & Therapeutics (2004) 75, 89–100; doi: 10.1016/j.clpt.2003.09.013
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the effect of age sex and rifampin administration on Intestinal and hepatic cytochrome p450 3a activity
Clinical Pharmacology & Therapeutics, 2003Co-Authors: Christopher J Gorski, Mitchell A. Hamman, Suda Vannaprasaht, Melissa A Bruce, Walter T AmbrosiusAbstract:Background The relative susceptibility of Intestinal and hepatic cytochrome P450 (CYP) 3A to induction by rifampin (INN, rifampicin), as a function of age and sex, was investigated with the CYP3A substrate midazolam. Methods Fourteen young women (mean age, 26 ± 4 years), 14 young men (mean age, 27 ± 4 years), 14 elderly women (mean age, 72 ± 5 years), and 10 elderly men (mean age, 70 ± 4 years) received simultaneous intravenous doses (0.05 mg/kg over a 30-minute period) and oral doses of midazolam (3-8 mg of a stable isotope, 15N3-midazolam) before and after 7 days of rifampin dosing (600 mg once daily in the evening). Serum and urine samples were assayed for midazolam, 15N3-midazolam, and metabolites by liquid chromatography–mass spectrometry. Results No significant difference (P ≥ .05) in the baseline systemic and oral clearance of midazolam was observed between male and female or young and old volunteers. Rifampin significantly (P < .0001) increased the systemic and oral clearance of midazolam from 0.44 ± 0.2 L · h/kg and 1.56 ± 0.8 L · h/kg to 0.96 ± 0.3 L · h/kg and 34.4 ± 21.2 L · h/kg, respectively. Likewise, the oral clearance of midazolam was significantly (P < .0001) increased in women and men, from 1.64 ± 0.87 L · kg/h and 1.46 ± 0.7 L · kg/h to 28.4 ± 13.2 L · kg/h and 41.6 ± 26.5 L · kg/h, respectively. A significant (P = .0023) effect of sex was noted in the extent of induction of the oral clearance of midazolam, being greater in men than in women. In contrast, the extent of midazolam systemic clearance induction was greater in women than in men (P = .0107). Age did not influence the extent of Intestinal and hepatic CYP3A induction as determined by the oral and systemic clearance of midazolam. Rifampin dosing significantly (P < .0001) reduced the oral Availability by 88%, from 0.32 ± 0.13 to 0.04 ± 0.02. Correspondingly, hepatic and Intestinal availabilities were significantly (P < .0001) reduced after rifampin administration. After rifampin, the correlation coefficient for the relationship between oral Availability and Intestinal Availability was significantly (P < .0001) reduced from 0.96 to 0.67, which reflects the increasing contribution of hepatic extraction to the determination of midazolam oral Availability. A significant nonlinear inverse relationship was observed between the percent change in systemic clearance of midazolam and the initial baseline midazolam systemic clearance (r = −0.68, N = 52, P < .0001). Likewise, a significant inverse relationship was observed between the percent change in oral clearance and the baseline oral clearance (r = −0.39, N = 52, P = .0041). A significant inverse relationship between the ratio of hepatic intrinsic clearance in the presence of rifampin to that in the absence of rifampin and the corresponding ratio of Intestinal intrinsic clearance was observed (Spearman correlation coefficient [r] = −0.68, P < .0001) and indicates that in a given individual the extent of induction was high at either the hepatic or the Intestinal site but not both. Conclusion Sex-related differences exist in the extent of Intestinal and hepatic CYP3A induction by rifampin. The extent of induction at hepatic and Intestinal sites was inversely dependent and reflected the independent regulation of CYP3A expression at these sites. The large interindividual variation in the extent of induction is explained in part by the variation in baseline expression of CYP3A. Sex-related differences in response to CYP3A inducers will be substrate-dependent and reflect the relative contribution of hepatic and Intestinal sites of metabolism. Clinical Pharmacology & Therapeutics (2003) 74, 275–287; doi: 10.1016/S0009-9236(03)00187-5
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hepatic and Intestinal cytochrome p450 3a activity in cirrhosis effects of transjugular intrahepatic portosystemic shunts
Hepatology, 2001Co-Authors: Naga Chalasani, Nilesh H Patel, Raymond E Galinsky, Christopher J Gorski, Stephen D. HallAbstract:Transjugular intrahepatic portosystemic shunt (TIPS) is performed to treat some complications of cirrhosis. This study investigated the effects of cirrhosis and TIPS on Intestinal and hepatic cytochrome P450 3A (CYP3A) activity. Nine volunteers were cirrhotic patients with TIPS, 9 were cirrhotic controls (matched for sex, age, etiology, and Child-Pugh class), and 9 were sex- and age-matched healthy volunteers. Simultaneous doses of midazolam were given intravenously (0.05 mg/kg) and orally (3 mg of [15N3]midazolam). Peripheral and portal venous blood samples were assayed for midazolam and [15N3]midazolam. The systemic clearance of midazolam was significantly greater (P [lt ] .05) in healthy volunteers (0.42 [plusmn] 0.10 L [middot] h[minus ]1 [middot] kg[minus ]1) compared with cirrhotic controls (0.20 [plusmn] 0.05) and with cirrhotic patients with TIPS (0.21 [plusmn] 0.09). Hepatic Availability followed the same trend. The bioAvailability of midazolam was significantly higher (P [lt ] .05) in cirrhotic patients with TIPS (0.76 [plusmn] 0.20) compared with cirrhotic controls (0.27 [plusmn] 0.14) and with healthy volunteers (0.30 [plusmn] 0.10). The Intestinal Availability was significantly greater (P [lt ] .05) in cirrhotic patients with TIPS (0.83 [plusmn] 0.17) compared with cirrhotic controls (0.32 [plusmn] 0.16) and with healthy volunteers (0.42[plusmn]0.15). As expected, hepatic CYP3A activity was reduced in cirrhosis. However, in cirrhotic patients with TIPS, there was a marked loss in first-pass metabolism of midazolam as a result of diminished Intestinal CYP3A activity. (HEPATOLOGY 2001;34:1103-1108.)
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the contribution of Intestinal and hepatic cyp3a to the interaction between midazolam and clarithromycin
Clinical Pharmacology & Therapeutics, 1998Co-Authors: Christopher J Gorski, Mitchell A. Hamman, David R Jones, Barbara D Haehnerdaniels, Edward M Omara, Stephen D. HallAbstract:Objective To assess the relative contribution of Intestinal and hepatic CYP3A inhibition to the interaction between the prototypic CYP3A substrates midazolam and clarithromycin. Methods On day 1, 16 volunteers (eight men and eight women; age range, 20 to 40 years; weight range, 45 to 100 kg) received simultaneous doses of midazolam intravenously (0.05 mg/kg over 30 minutes) and orally (4 mg of a stable isotope, 15N3-midazolam). Starting on day 2, 500 mg clarithromycin was administered orally twice daily for 7 days. On day 8, intravenous and oral doses of midazolam were administered 2 hours after the final clarithromycin dose. Blood and urine samples were assayed for midazolam, 15N3-midazolam, and metabolites by gas chromatography-mass spectrometry. Results There was no significant (p > 0.05) difference in the urinary excretion of 1′-hydroxymidazolam after intravenous and oral dosing on day 1 or day 8, indicating that the oral dose was completely absorbed into the gut wall. The oral clearance of midazolam was found to be significantly greater in female subjects (1.9 ± 1.0 versus 1.0 ± 0.3 L/hr/kg; p < 0.05) than in male subjects but not systemic clearance (0.35 ± 0.1 versus 0.44 ± 0.1 L/hr/kg). For women not receiving oral contraceptives (n = 6) a significant gender-related difference was observed for systemic and oral clearance and for area under the curve and elimination half-life after oral administration. A significant (p < 0.05) reduction in the systemic clearance of midazolam from 28 ± 9 L/hr to 10 ± 3 L/hr occurred after clarithromycin administration. Oral midazolam Availability was significantly increased from 0.31 ± 0.1 to 0.75 +- 0.2 after clarithromycin dosing. Likewise, Intestinal and oral Availability were significantly increased from 0.42 ± 0.2 to 0.83 ± 0.2 and from 0.74 ± 0.1 to 0.90 ± 0.04, respectively. A significant correlation was observed between Intestinal and oral Availability (n = 32, r = 0.98, p < 0.05). After clarithromycin administration, a significant correlation was observed between the initial hepatic or Intestinal Availability and the relative increase in hepatic or Intestinal Availability, respectively. Female subjects exhibited a greater extent of interaction after oral and intravenous dosing than male subjects (p < 0.05). Conclusion These data indicate that in addition to the liver, the intestine is a major site of the interaction between oral midazolam and clarithromycin. Interindividual variability in first-pass extraction of high-affinity CYP3A substrates such as midazolam is primarily a function of Intestinal enzyme activity. Clinical Pharmacology & Therapeutics (1998) 64, 133–143; doi:
Sandy K Pang - One of the best experts on this subject based on the ideXlab platform.
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Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and Q Gut Model
2020Co-Authors: Sandy K Pang, Edwin C Y ChowAbstract:ABSTRACT: Physiologically based pharmacokinetic (PBPK) models for the intestine, comprising of different flow rates perfusing the enterocyte region, were revisited for appraisal of flow affects on the Intestinal Availability (F I ) and, in turn, the systemic Availability (F sys ) and Intestinal versus liver contribution to the first-pass effect during oral drug absorption. The traditional model (TM), segregated flow model (SFM), and effective flow (Q Gut ) model stipulate that 1.0, ϳ0.05 to 0.3, and <0.484؋ of the total Intestinal flow, respectively, reach the enterocyte region that houses metabolically active and transporter-enriched enterocytes. The fractional flow rate to the enterocyte region (f Q ), when examined under varying experimental conditions, was found to range from 0.024 to 0.2 for the SFM and 0.065 to 0.43 for the Q Gut model. Appraisal of these flow Intestinal models, when used in combination with whole-body PBPK models, showed the ranking as SFM < Q Gut model < TM in the description of F I , and the same ranking existed for the contribution of the intestine to first-pass removal. However, the ranking for the predicted contribution of hepatic metabolism, when present, to firstpass removal was the opposite: SFM > Q Gut model > TM. The findings suggest that the f Q value strongly influences the rate of Intestinal metabolism (F I and F sys ) and indirectly affects the rate of liver metabolism due to substrate sparing effect. Thus, the f Q value in the Intestinal flow models pose serious implications on the interpretation of data on the first-pass effect and oral absorption of drugs
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commentary theoretical predictions of flow effects on Intestinal and systemic Availability in physiologically based pharmacokinetic intestine models the traditional model segregated flow model and qgut model
Drug Metabolism and Disposition, 2012Co-Authors: Sandy K Pang, Edwin C Y ChowAbstract:Physiologically based pharmacokinetic (PBPK) models for the intestine, comprising of different flow rates perfusing the enterocyte region, were revisited for appraisal of flow affects on the Intestinal Availability (FI) and, in turn, the systemic Availability (Fsys) and Intestinal versus liver contribution to the first-pass effect during oral drug absorption. The traditional model (TM), segregated flow model (SFM), and effective flow (QGut) model stipulate that 1.0, ∼0.05 to 0.3, and ≤0.484× of the total Intestinal flow, respectively, reach the enterocyte region that houses metabolically active and transporter-enriched enterocytes. The fractional flow rate to the enterocyte region (fQ), when examined under varying experimental conditions, was found to range from 0.024 to 0.2 for the SFM and 0.065 to 0.43 for the QGut model. Appraisal of these flow Intestinal models, when used in combination with whole-body PBPK models, showed the ranking as SFM QGut model > TM. The findings suggest that the fQ value strongly influences the rate of Intestinal metabolism (FI and Fsys) and indirectly affects the rate of liver metabolism due to substrate sparing effect. Thus, the fQ value in the Intestinal flow models pose serious implications on the interpretation of data on the first-pass effect and oral absorption of drugs.
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pbpk modeling of Intestinal and liver enzymes and transporters in drug absorption and sequential metabolism
Current Drug Metabolism, 2010Co-Authors: Shu Chen, Edwin C Y Chow, Sandy K PangAbstract:Experimental strategies have long been applied for in vitro or in vivo evaluation of the effect of transporters and/or enzymes on the bioAvailability. However, the lack of specific inhibitors or inducers of transporters and enzymes and the multiplicity of nuclear receptors in gene regulation and cross-talk have led to compromised assessments of these effects in vivo. These and other causes have resulted in confusion and controversy in transporter-enzyme interplay. In this review, physiologically-based pharmacokinetic (PBPK) Intestinal and liver models are utilized to predict the contributions of enzymes and transporters on Intestinal Availability (FI) and hepatic Availability (FH), with the aim to fully understand the impact of these variables on bioAvailability (Fsys) in vivo. We emphasize the often overlooked impact of influx and efflux clearances, and apply the PBPK models and their solutions to examine individual organ clearances of the intestine and liver. In order to accurately predict oral bioAvailability, these organ models are incorporated into the whole body PBPK model, and additional complicated scenarios such as segmental differences and zonal heterogeneity of transporters and enzymes in the intestine and liver, and segregated blood flow patterns of the intestine are further discussed. The sequential metabolism of a drug to form primary and secondary metabolites in the first-pass organs is considered in PBPK modeling, revealing that the segregated flow model (SFM) of the intestine is more appropriate than the traditional PBPK Intestinal model (TM). Examples are included to highlight the potential application of these PBPK models on the quantitative prediction of bioAvailability.
Edwin C Y Chow - One of the best experts on this subject based on the ideXlab platform.
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Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and Q Gut Model
2020Co-Authors: Sandy K Pang, Edwin C Y ChowAbstract:ABSTRACT: Physiologically based pharmacokinetic (PBPK) models for the intestine, comprising of different flow rates perfusing the enterocyte region, were revisited for appraisal of flow affects on the Intestinal Availability (F I ) and, in turn, the systemic Availability (F sys ) and Intestinal versus liver contribution to the first-pass effect during oral drug absorption. The traditional model (TM), segregated flow model (SFM), and effective flow (Q Gut ) model stipulate that 1.0, ϳ0.05 to 0.3, and <0.484؋ of the total Intestinal flow, respectively, reach the enterocyte region that houses metabolically active and transporter-enriched enterocytes. The fractional flow rate to the enterocyte region (f Q ), when examined under varying experimental conditions, was found to range from 0.024 to 0.2 for the SFM and 0.065 to 0.43 for the Q Gut model. Appraisal of these flow Intestinal models, when used in combination with whole-body PBPK models, showed the ranking as SFM < Q Gut model < TM in the description of F I , and the same ranking existed for the contribution of the intestine to first-pass removal. However, the ranking for the predicted contribution of hepatic metabolism, when present, to firstpass removal was the opposite: SFM > Q Gut model > TM. The findings suggest that the f Q value strongly influences the rate of Intestinal metabolism (F I and F sys ) and indirectly affects the rate of liver metabolism due to substrate sparing effect. Thus, the f Q value in the Intestinal flow models pose serious implications on the interpretation of data on the first-pass effect and oral absorption of drugs
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commentary theoretical predictions of flow effects on Intestinal and systemic Availability in physiologically based pharmacokinetic intestine models the traditional model segregated flow model and qgut model
Drug Metabolism and Disposition, 2012Co-Authors: Sandy K Pang, Edwin C Y ChowAbstract:Physiologically based pharmacokinetic (PBPK) models for the intestine, comprising of different flow rates perfusing the enterocyte region, were revisited for appraisal of flow affects on the Intestinal Availability (FI) and, in turn, the systemic Availability (Fsys) and Intestinal versus liver contribution to the first-pass effect during oral drug absorption. The traditional model (TM), segregated flow model (SFM), and effective flow (QGut) model stipulate that 1.0, ∼0.05 to 0.3, and ≤0.484× of the total Intestinal flow, respectively, reach the enterocyte region that houses metabolically active and transporter-enriched enterocytes. The fractional flow rate to the enterocyte region (fQ), when examined under varying experimental conditions, was found to range from 0.024 to 0.2 for the SFM and 0.065 to 0.43 for the QGut model. Appraisal of these flow Intestinal models, when used in combination with whole-body PBPK models, showed the ranking as SFM QGut model > TM. The findings suggest that the fQ value strongly influences the rate of Intestinal metabolism (FI and Fsys) and indirectly affects the rate of liver metabolism due to substrate sparing effect. Thus, the fQ value in the Intestinal flow models pose serious implications on the interpretation of data on the first-pass effect and oral absorption of drugs.
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pbpk modeling of Intestinal and liver enzymes and transporters in drug absorption and sequential metabolism
Current Drug Metabolism, 2010Co-Authors: Shu Chen, Edwin C Y Chow, Sandy K PangAbstract:Experimental strategies have long been applied for in vitro or in vivo evaluation of the effect of transporters and/or enzymes on the bioAvailability. However, the lack of specific inhibitors or inducers of transporters and enzymes and the multiplicity of nuclear receptors in gene regulation and cross-talk have led to compromised assessments of these effects in vivo. These and other causes have resulted in confusion and controversy in transporter-enzyme interplay. In this review, physiologically-based pharmacokinetic (PBPK) Intestinal and liver models are utilized to predict the contributions of enzymes and transporters on Intestinal Availability (FI) and hepatic Availability (FH), with the aim to fully understand the impact of these variables on bioAvailability (Fsys) in vivo. We emphasize the often overlooked impact of influx and efflux clearances, and apply the PBPK models and their solutions to examine individual organ clearances of the intestine and liver. In order to accurately predict oral bioAvailability, these organ models are incorporated into the whole body PBPK model, and additional complicated scenarios such as segmental differences and zonal heterogeneity of transporters and enzymes in the intestine and liver, and segregated blood flow patterns of the intestine are further discussed. The sequential metabolism of a drug to form primary and secondary metabolites in the first-pass organs is considered in PBPK modeling, revealing that the segregated flow model (SFM) of the intestine is more appropriate than the traditional PBPK Intestinal model (TM). Examples are included to highlight the potential application of these PBPK models on the quantitative prediction of bioAvailability.
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inhibition of human Intestinal wall metabolism by macrolide antibiotics effect of clarithromycin on cytochrome p450 3a4 5 activity and expression
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Amar Pinto, Dhanashri Kolwankar, Suthat Liangpunsakul, Million Arefayene, Christopher J Gorski, Mitchell A. Hamman, Naga Chalasani, Ying-hong Wang, Todd C. Skaar, Stephen D. HallAbstract:Background Clarithromycin increases both hepatic and Intestinal Availability of the selective cytochrome P450 (CYP) 3A probe midazolam. This study was designed to identify determinants of variability in the extent of Intestinal wall CYP3A inhibition by clarithromycin, such as CYP3A5 genotype, and the mechanism of inhibition. Methods Ten healthy volunteers received 500 mg oral clarithromycin twice a day for 7 days. Before and after administration of clarithromycin, small-bowel mucosal biopsy specimens were obtained endoscopically. Intestinal CYP3A activity was determined from the rate of 1′-hydroxymidazolam and 4-hydroxymidazolam formation by incubation of small-bowel homogenate with midazolam (25 Μmol/L) and NADPH for 5 minutes. Intestinal CYP3A4 and CYP3A5 messenger ribonucleic acid was quantified by real-time reverse transcriptase-polymerase chain reaction. Intestinal CYP3A4 and CYP3A5 protein concentrations were determined by immunoblotting. Serum and homogenate concentrations of midazolam, clarithromycin, and metabolites were determined by liquid chromatography-mass spectrometry. CYP3A5 genotype was determined by real-time polymerase chain reaction. Results The formation of 1′-hydroxymidazolam (1.36 ± 0.46 pmol · min−1 · mg−1 at baseline versus 0.35 ± 0.16 pmol · min−1 · mg−1 after administration) and 4-hydroxymidazolam (0.39 ± 0.12 pmol · min−1 · mg−1 at baseline versus 0.12 ± 0.05 pmol · min−1 · mg−1 after administration) was significantly (P < .001) reduced after clarithromycin administration. Clarithromycin administration did not result in a significant change in Intestinal CYP3A4 and CYP3A5 messenger ribonucleic acid and protein expression. All subjects had detectable serum clarithromycin concentrations after 7 days of clarithromycin (3.71 ± 2.43 Μmol/L). The mean concentration of clarithromycin in the Intestinal biopsy homogenate was 1.2 ± 0.7 nmol/L (range, 0.42–2.39 nmol/L). Compared with CYP3A5 nonexpressers, subjects with at least 1 CYP3A5*1 allele (CYP3A5 expressers) had greater inhibition of Intestinal CYP3A activity after treatment with clarithromycin. There was a strong linear relationship between the decrease in Intestinal CYP3A activity and baseline catalytic activity (R2 = 0.9). Conclusion Baseline Intestinal activity of CYP3A4 was a key determinant of variability of the inhibitory effect of clarithromycin among individuals. CYP3A5*1 alleles were associated with greater baseline Intestinal CYP3A activity and, therefore, greater extent of inhibition. The primary in vivo mechanism was not rapidly reversible competitive or irreversible inhibition but was likely formation of metabolic intermediate complexes. Clinical Pharmacology & Therapeutics (2005) 77, 178–188; doi: 10.1016/j.clpt.2004.10.002
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the effect of echinacea echinacea purpurea root on cytochrome p450 activity in vivo
Clinical Pharmacology & Therapeutics, 2004Co-Authors: Christopher J Gorski, Mitchell A. Hamman, J. Hilligoss, Shiew-mei Huang, Amar G. PintoAbstract:Background Echinacea is a widely available over-the-counter herbal remedy. Tinctures of echinacea have been shown to inhibit cytochrome P450 (CYP) in vitro. The effect of echinacea (Echinacea purpurea root) on CYP activity in vivo was assessed by use of the CYP probe drugs caffeine (CYP1A2), tolbutamide (CYP2C9), dextromethorphan (CYP2D6), and midazolam (hepatic and Intestinal CYP3A). Methods Twelve healthy subjects (6 men) completed this 2-period, open-label, fixed-schedule study. Caffeine, tolbutamide, dextromethorphan, and oral and intravenous midazolam were administered before and after a short course of echinacea (400 mg 4 times a day for 8 days) to determine in vivo CYP activities. Results Echinacea administration significantly increased the systemic clearance of midazolam by 34%, from 32 ± 7 L/h to 43 ± 16 L/h (P = .003; 90% confidence interval [CI], 116%-150%), and significantly reduced the midazolam area under the concentration-time curve by 23%, from 127 ± 36 μg · h/L to 102 ± 43 μg · h/L (P = .024; 90% CI, 63%-88%). In contrast, the oral clearance of midazolam was not significantly altered (P = .655; 90% CI, 75%-124%), 137 ± 19 L/h compared with 146 ± 71 L/h. The oral Availability of midazolam after echinacea dosing was significantly increased (P = .028; 90% CI, 108%-153%), from 0.23 ± 0.06 to 0.33 ± 0.13. Hepatic Availability (0.72 ± 0.08 versus 0.61 ± 0.16; P = .006; 90% CI, 73%-90%) and Intestinal Availability (0.33 ± 0.11 versus 0.61 ± 0.38; P = .015; 90% CI, 125%-203%) were significantly altered in opposite directions. Echinacea dosing significantly reduced the oral clearance of caffeine, from 6.6 ± 3.8 L/h to 4.9 ± 2.3 L/h (P = .049; 90% CI, 58%-96%). The oral clearance of tolbutamide was reduced by 11%, from 0.81 ± 0.18 L/h to 0.72 ± 0.19 L/h, but this change was not considered to be clinically relevant because the 90% CIs were within the 80% to 125% range. The oral clearance of dextromethorphan in 11 CYP2D6 extensive metabolizers was not affected by echinacea dosing (1289 ± 414 L/h compared with 1281 ± 483 L/h; P = .732; 90% CI, 89%-108%). Conclusions Echinacea (E purpurea root) reduced the oral clearance of substrates of CYP1A2 but not the oral clearance of substrates of CYP2C9 and CYP2D6. Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and Intestinal sites. The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and Intestinal sites. Caution should be used when echinacea is coadministered with drugs dependent on CYP3A or CYP1A2 for their elimination. Clinical Pharmacology & Therapeutics (2004) 75, 89–100; doi: 10.1016/j.clpt.2003.09.013
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the effect of age sex and rifampin administration on Intestinal and hepatic cytochrome p450 3a activity
Clinical Pharmacology & Therapeutics, 2003Co-Authors: Christopher J Gorski, Mitchell A. Hamman, Suda Vannaprasaht, Melissa A Bruce, Walter T AmbrosiusAbstract:Background The relative susceptibility of Intestinal and hepatic cytochrome P450 (CYP) 3A to induction by rifampin (INN, rifampicin), as a function of age and sex, was investigated with the CYP3A substrate midazolam. Methods Fourteen young women (mean age, 26 ± 4 years), 14 young men (mean age, 27 ± 4 years), 14 elderly women (mean age, 72 ± 5 years), and 10 elderly men (mean age, 70 ± 4 years) received simultaneous intravenous doses (0.05 mg/kg over a 30-minute period) and oral doses of midazolam (3-8 mg of a stable isotope, 15N3-midazolam) before and after 7 days of rifampin dosing (600 mg once daily in the evening). Serum and urine samples were assayed for midazolam, 15N3-midazolam, and metabolites by liquid chromatography–mass spectrometry. Results No significant difference (P ≥ .05) in the baseline systemic and oral clearance of midazolam was observed between male and female or young and old volunteers. Rifampin significantly (P < .0001) increased the systemic and oral clearance of midazolam from 0.44 ± 0.2 L · h/kg and 1.56 ± 0.8 L · h/kg to 0.96 ± 0.3 L · h/kg and 34.4 ± 21.2 L · h/kg, respectively. Likewise, the oral clearance of midazolam was significantly (P < .0001) increased in women and men, from 1.64 ± 0.87 L · kg/h and 1.46 ± 0.7 L · kg/h to 28.4 ± 13.2 L · kg/h and 41.6 ± 26.5 L · kg/h, respectively. A significant (P = .0023) effect of sex was noted in the extent of induction of the oral clearance of midazolam, being greater in men than in women. In contrast, the extent of midazolam systemic clearance induction was greater in women than in men (P = .0107). Age did not influence the extent of Intestinal and hepatic CYP3A induction as determined by the oral and systemic clearance of midazolam. Rifampin dosing significantly (P < .0001) reduced the oral Availability by 88%, from 0.32 ± 0.13 to 0.04 ± 0.02. Correspondingly, hepatic and Intestinal availabilities were significantly (P < .0001) reduced after rifampin administration. After rifampin, the correlation coefficient for the relationship between oral Availability and Intestinal Availability was significantly (P < .0001) reduced from 0.96 to 0.67, which reflects the increasing contribution of hepatic extraction to the determination of midazolam oral Availability. A significant nonlinear inverse relationship was observed between the percent change in systemic clearance of midazolam and the initial baseline midazolam systemic clearance (r = −0.68, N = 52, P < .0001). Likewise, a significant inverse relationship was observed between the percent change in oral clearance and the baseline oral clearance (r = −0.39, N = 52, P = .0041). A significant inverse relationship between the ratio of hepatic intrinsic clearance in the presence of rifampin to that in the absence of rifampin and the corresponding ratio of Intestinal intrinsic clearance was observed (Spearman correlation coefficient [r] = −0.68, P < .0001) and indicates that in a given individual the extent of induction was high at either the hepatic or the Intestinal site but not both. Conclusion Sex-related differences exist in the extent of Intestinal and hepatic CYP3A induction by rifampin. The extent of induction at hepatic and Intestinal sites was inversely dependent and reflected the independent regulation of CYP3A expression at these sites. The large interindividual variation in the extent of induction is explained in part by the variation in baseline expression of CYP3A. Sex-related differences in response to CYP3A inducers will be substrate-dependent and reflect the relative contribution of hepatic and Intestinal sites of metabolism. Clinical Pharmacology & Therapeutics (2003) 74, 275–287; doi: 10.1016/S0009-9236(03)00187-5
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the contribution of Intestinal and hepatic cyp3a to the interaction between midazolam and clarithromycin
Clinical Pharmacology & Therapeutics, 1998Co-Authors: Christopher J Gorski, Mitchell A. Hamman, David R Jones, Barbara D Haehnerdaniels, Edward M Omara, Stephen D. HallAbstract:Objective To assess the relative contribution of Intestinal and hepatic CYP3A inhibition to the interaction between the prototypic CYP3A substrates midazolam and clarithromycin. Methods On day 1, 16 volunteers (eight men and eight women; age range, 20 to 40 years; weight range, 45 to 100 kg) received simultaneous doses of midazolam intravenously (0.05 mg/kg over 30 minutes) and orally (4 mg of a stable isotope, 15N3-midazolam). Starting on day 2, 500 mg clarithromycin was administered orally twice daily for 7 days. On day 8, intravenous and oral doses of midazolam were administered 2 hours after the final clarithromycin dose. Blood and urine samples were assayed for midazolam, 15N3-midazolam, and metabolites by gas chromatography-mass spectrometry. Results There was no significant (p > 0.05) difference in the urinary excretion of 1′-hydroxymidazolam after intravenous and oral dosing on day 1 or day 8, indicating that the oral dose was completely absorbed into the gut wall. The oral clearance of midazolam was found to be significantly greater in female subjects (1.9 ± 1.0 versus 1.0 ± 0.3 L/hr/kg; p < 0.05) than in male subjects but not systemic clearance (0.35 ± 0.1 versus 0.44 ± 0.1 L/hr/kg). For women not receiving oral contraceptives (n = 6) a significant gender-related difference was observed for systemic and oral clearance and for area under the curve and elimination half-life after oral administration. A significant (p < 0.05) reduction in the systemic clearance of midazolam from 28 ± 9 L/hr to 10 ± 3 L/hr occurred after clarithromycin administration. Oral midazolam Availability was significantly increased from 0.31 ± 0.1 to 0.75 +- 0.2 after clarithromycin dosing. Likewise, Intestinal and oral Availability were significantly increased from 0.42 ± 0.2 to 0.83 ± 0.2 and from 0.74 ± 0.1 to 0.90 ± 0.04, respectively. A significant correlation was observed between Intestinal and oral Availability (n = 32, r = 0.98, p < 0.05). After clarithromycin administration, a significant correlation was observed between the initial hepatic or Intestinal Availability and the relative increase in hepatic or Intestinal Availability, respectively. Female subjects exhibited a greater extent of interaction after oral and intravenous dosing than male subjects (p < 0.05). Conclusion These data indicate that in addition to the liver, the intestine is a major site of the interaction between oral midazolam and clarithromycin. Interindividual variability in first-pass extraction of high-affinity CYP3A substrates such as midazolam is primarily a function of Intestinal enzyme activity. Clinical Pharmacology & Therapeutics (1998) 64, 133–143; doi:
