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Yuichi Sugiyama - One of the best experts on this subject based on the ideXlab platform.
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extrapolation of in vivo Hepatic Clearance from in vitro uptake Clearance by suspended human hepatocytes for anionic drugs with high binding to human albumin improvement of in vitro to in vivo extrapolation by considering the albumin mediated Hepatic
Drug Metabolism and Disposition, 2019Co-Authors: Seiji Miyauchi, Yuichi SugiyamaAbstract:We investigated whether human serum albumin (HSA) in suspended human hepatocytes would affect the uptake Clearance of anionic drugs with high binding to HSA and improve the extrapolation of in vivo Hepatic Clearance from in vitro uptake Clearance by the hepatocytes via the “albumin-mediated” Hepatic uptake mechanism. The uptake Clearances for total forms (PSinf) and for unbound forms (PSu,inf) of 11 anionic drugs [all of which were organic anion-transporting polypeptide (OATP) substrates] were determined with suspended human hepatocytes in varying concentrations of HSA. The fraction of unbound drugs (fu) was determined using an equilibrium dialysis at the various HSA concentrations. The PSinf values decreased with increasing concentrations of HSA, whereas the unbound uptake Clearances (PSu,inf(+) = PSinf/ fu) in the presence of HSA increased substantially, thus demonstrating the “albumin-mediated” Hepatic uptake mechanism. The relationships between PSinf and HSA concentration were well described by the previously proposed facilitated-dissociation model, in which the drug–albumin complex interacts with the cell surface, enhancing the dissociation of the complex and providing unbound drug for Hepatic uptake. Furthermore, the PSu,inf (+) values in in vivo conditions (at 5% HSA) were predicted from those obtained in isolated hepatocytes on the basis of the facilitated-dissociation model, revealing compatibility with the overall Hepatic intrinsic Clearance in vivo. We conclude that the “facilitated-dissociation” model is useful for describing the “albumin-mediated” Hepatic uptake phenomenon of OATP drugs and to predict Hepatic uptake Clearance in vivo.
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relative activity factor raf based scaling of uptake Clearance mediated by organic anion transporting polypeptide oatp 1b1 and oatp1b3 in human hepatocytes
Molecular Pharmaceutics, 2018Co-Authors: Saki Izumi, Kazuya Maeda, Hiroyuki Kusuhara, Yoshitane Nozaki, Koichiro Hotta, Toshiki Mochizuki, Takafumi Komori, Yuichi SugiyamaAbstract:In vitro–in vivo extrapolation based on uptake Clearance determined in human hepatocytes has been used to predict in vivo Hepatic Clearance of organic anion transporting polypeptide (OATP) substrates. This study evaluated the relative activity factor (RAF) approach to extrapolate active uptake Clearance in transporter-transfected cell systems (CLuptake) to that in human hepatocyte suspensions (PSinf,act). RAF values for OATP1B1 and OATP1B3 were determined in two batches of cryopreserved human hepatocytes using estrone-3-sulfate and cholecystokinin octapeptide as reference substrates, respectively. Fourteen OATP1B substrate drugs selected (atorvastatin, bosentan, cerivastatin, fexofenadine, fluvastatin, glibenclamide, irbesartan, nateglinide, pitavastatin, pravastatin, rosuvastatin, telmisartan, torasemide, and valsartan) showed temperature-dependent uptake in human hepatocytes. In transporter-transfected cells, OATP1B1- and OATP1B3-mediated uptake was observed in all compounds except for telmisartan. RAF-...
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clinical significance of organic anion transporting polypeptides oatps in drug disposition their roles in Hepatic Clearance and intestinal absorption
Biopharmaceutics & Drug Disposition, 2013Co-Authors: Yoshihisa Shitara, Kazuya Maeda, Kazuaki Ikejiri, Kenta Yoshida, Toshiharu Horie, Yuichi SugiyamaAbstract:Organic anion transporting polypeptide (OATP) family transporters accept a number of drugs and are increasingly being recognized as important factors in governing drug and metabolite pharmacokinetics. OATP1B1 and OATP1B3 play an important role in Hepatic drug uptake while OATP2B1 and OATP1A2 might be key players in intestinal absorption and transport across blood-brain barrier of drugs, respectively. To understand the importance of OATPs in the Hepatic Clearance of drugs, the rate-determining process for elimination should be considered; for some drugs, Hepatic uptake Clearance rather than metabolic intrinsic Clearance is the more important determinant of Hepatic Clearances. The importance of the unbound concentration ratio (liver/blood), K(p,uu) , of drugs, which is partly governed by OATPs, is exemplified in interpreting the difference in the IC(50) of statins between the hepatocyte and microsome systems for the inhibition of HMG-CoA reductase activity. The intrinsic activity and/or expression level of OATPs are affected by genetic polymorphisms and drug-drug interactions. Their effects on the elimination rate or intestinal absorption rate of drugs may sometimes depend on the substrate drug. This is partly because of the different contribution of OATP isoforms to Clearance or intestinal absorption. When the contribution of the OATP-mediated pathway is substantial, the pharmacokinetics of substrate drugs should be greatly affected. This review describes the estimation of the contribution of OATP1B1 to the total Hepatic uptake of drugs from the data of fold-increases in the plasma concentration of substrate drugs by the genetic polymorphism of this transporter. To understand the importance of the OATP family transporters, modeling and simulation with a physiologically based pharmacokinetic model are helpful.
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clinical significance of organic anion transporting polypeptides oatps in drug disposition their roles in Hepatic Clearance and intestinal absorption
Biopharmaceutics & Drug Disposition, 2013Co-Authors: Yoshihisa Shitara, Kazuya Maeda, Kazuaki Ikejiri, Kenta Yoshida, Toshiharu Horie, Yuichi SugiyamaAbstract:Organic anion transporting polypeptide (OATP) family transporters accept a number of drugs and are increasingly being recognized as important factors in governing drug and metabolite pharmacokinetics. OATP1B1 and OATP1B3 play an important role in Hepatic drug uptake while OATP2B1 and OATP1A2 might be key players in intestinal absorption and transport across blood–brain barrier of drugs, respectively. To understand the importance of OATPs in the Hepatic Clearance of drugs, the rate-determining process for elimination should be considered; for some drugs, Hepatic uptake Clearance rather than metabolic intrinsic Clearance is the more important determinant of Hepatic Clearances. The importance of the unbound concentration ratio (liver/blood), Kp,uu, of drugs, which is partly governed by OATPs, is exemplified in interpreting the difference in the IC50 of statins between the hepatocyte and microsome systems for the inhibition of HMG-CoA reductase activity. The intrinsic activity and/or expression level of OATPs are affected by genetic polymorphisms and drug–drug interactions. Their effects on the elimination rate or intestinal absorption rate of drugs may sometimes depend on the substrate drug. This is partly because of the different contribution of OATP isoforms to Clearance or intestinal absorption. When the contribution of the OATP-mediated pathway is substantial, the pharmacokinetics of substrate drugs should be greatly affected. This review describes the estimation of the contribution of OATP1B1 to the total Hepatic uptake of drugs from the data of fold-increases in the plasma concentration of substrate drugs by the genetic polymorphism of this transporter. To understand the importance of the OATP family transporters, modeling and simulation with a physiologically based pharmacokinetic model are helpful. Copyright © 2012 John Wiley & Sons, Ltd.
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identification of the rate determining process in the Hepatic Clearance of atorvastatin in a clinical cassette microdosing study
Clinical Pharmacology & Therapeutics, 2011Co-Authors: Kazuya Maeda, Kenta Yoshida, Y Ikeda, Tomoe Fujita, Y Azuma, Y Haruyama, Naoe Yamane, Yuji Kumagai, Yuichi SugiyamaAbstract:Clearance of atorvastatin occurs through Hepatic uptake by organic anion transporting polypeptides (OATPs) and subsequent metabolism by cytochrome P450 (CYP) 3A4. To demonstrate the relative importance of OATPs and CYP3A4 in the Hepatic elimination of atorvastatin in vivo, a clinical cassette microdose study was performed. A cocktail consisting of a microdose of atorvastatin along with probe substrates for OATPs (pravastatin) and CYP3A4 (midazolam) was orally administered to eight healthy volunteers. The pharmacokinetics of this cocktail was observed at baseline, after an oral dose of 600 mg rifampicin (an inhibitor of OATPs), and after an intravenous dose of 200 mg itraconazole (a CYP3A4 inhibitor). Rifampicin increased the pravastatin dose-normalized area under the plasma concentration-time curve (AUC) (4.6-fold), and itraconazole significantly increased the midazolam dose-normalized AUC (1.7-fold). The atorvastatin dose-normalized AUC increased 12-fold when coadministered with rifampicin but did not change when coadministered with itraconazole. These results indicate that Hepatic uptake via OATPs makes the dominant contribution to the Hepatic elimination of atorvastatin at a subtherapeutic microdose.
Kazuya Maeda - One of the best experts on this subject based on the ideXlab platform.
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relative activity factor raf based scaling of uptake Clearance mediated by organic anion transporting polypeptide oatp 1b1 and oatp1b3 in human hepatocytes
Molecular Pharmaceutics, 2018Co-Authors: Saki Izumi, Kazuya Maeda, Hiroyuki Kusuhara, Yoshitane Nozaki, Koichiro Hotta, Toshiki Mochizuki, Takafumi Komori, Yuichi SugiyamaAbstract:In vitro–in vivo extrapolation based on uptake Clearance determined in human hepatocytes has been used to predict in vivo Hepatic Clearance of organic anion transporting polypeptide (OATP) substrates. This study evaluated the relative activity factor (RAF) approach to extrapolate active uptake Clearance in transporter-transfected cell systems (CLuptake) to that in human hepatocyte suspensions (PSinf,act). RAF values for OATP1B1 and OATP1B3 were determined in two batches of cryopreserved human hepatocytes using estrone-3-sulfate and cholecystokinin octapeptide as reference substrates, respectively. Fourteen OATP1B substrate drugs selected (atorvastatin, bosentan, cerivastatin, fexofenadine, fluvastatin, glibenclamide, irbesartan, nateglinide, pitavastatin, pravastatin, rosuvastatin, telmisartan, torasemide, and valsartan) showed temperature-dependent uptake in human hepatocytes. In transporter-transfected cells, OATP1B1- and OATP1B3-mediated uptake was observed in all compounds except for telmisartan. RAF-...
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clinical significance of organic anion transporting polypeptides oatps in drug disposition their roles in Hepatic Clearance and intestinal absorption
Biopharmaceutics & Drug Disposition, 2013Co-Authors: Yoshihisa Shitara, Kazuya Maeda, Kazuaki Ikejiri, Kenta Yoshida, Toshiharu Horie, Yuichi SugiyamaAbstract:Organic anion transporting polypeptide (OATP) family transporters accept a number of drugs and are increasingly being recognized as important factors in governing drug and metabolite pharmacokinetics. OATP1B1 and OATP1B3 play an important role in Hepatic drug uptake while OATP2B1 and OATP1A2 might be key players in intestinal absorption and transport across blood-brain barrier of drugs, respectively. To understand the importance of OATPs in the Hepatic Clearance of drugs, the rate-determining process for elimination should be considered; for some drugs, Hepatic uptake Clearance rather than metabolic intrinsic Clearance is the more important determinant of Hepatic Clearances. The importance of the unbound concentration ratio (liver/blood), K(p,uu) , of drugs, which is partly governed by OATPs, is exemplified in interpreting the difference in the IC(50) of statins between the hepatocyte and microsome systems for the inhibition of HMG-CoA reductase activity. The intrinsic activity and/or expression level of OATPs are affected by genetic polymorphisms and drug-drug interactions. Their effects on the elimination rate or intestinal absorption rate of drugs may sometimes depend on the substrate drug. This is partly because of the different contribution of OATP isoforms to Clearance or intestinal absorption. When the contribution of the OATP-mediated pathway is substantial, the pharmacokinetics of substrate drugs should be greatly affected. This review describes the estimation of the contribution of OATP1B1 to the total Hepatic uptake of drugs from the data of fold-increases in the plasma concentration of substrate drugs by the genetic polymorphism of this transporter. To understand the importance of the OATP family transporters, modeling and simulation with a physiologically based pharmacokinetic model are helpful.
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clinical significance of organic anion transporting polypeptides oatps in drug disposition their roles in Hepatic Clearance and intestinal absorption
Biopharmaceutics & Drug Disposition, 2013Co-Authors: Yoshihisa Shitara, Kazuya Maeda, Kazuaki Ikejiri, Kenta Yoshida, Toshiharu Horie, Yuichi SugiyamaAbstract:Organic anion transporting polypeptide (OATP) family transporters accept a number of drugs and are increasingly being recognized as important factors in governing drug and metabolite pharmacokinetics. OATP1B1 and OATP1B3 play an important role in Hepatic drug uptake while OATP2B1 and OATP1A2 might be key players in intestinal absorption and transport across blood–brain barrier of drugs, respectively. To understand the importance of OATPs in the Hepatic Clearance of drugs, the rate-determining process for elimination should be considered; for some drugs, Hepatic uptake Clearance rather than metabolic intrinsic Clearance is the more important determinant of Hepatic Clearances. The importance of the unbound concentration ratio (liver/blood), Kp,uu, of drugs, which is partly governed by OATPs, is exemplified in interpreting the difference in the IC50 of statins between the hepatocyte and microsome systems for the inhibition of HMG-CoA reductase activity. The intrinsic activity and/or expression level of OATPs are affected by genetic polymorphisms and drug–drug interactions. Their effects on the elimination rate or intestinal absorption rate of drugs may sometimes depend on the substrate drug. This is partly because of the different contribution of OATP isoforms to Clearance or intestinal absorption. When the contribution of the OATP-mediated pathway is substantial, the pharmacokinetics of substrate drugs should be greatly affected. This review describes the estimation of the contribution of OATP1B1 to the total Hepatic uptake of drugs from the data of fold-increases in the plasma concentration of substrate drugs by the genetic polymorphism of this transporter. To understand the importance of the OATP family transporters, modeling and simulation with a physiologically based pharmacokinetic model are helpful. Copyright © 2012 John Wiley & Sons, Ltd.
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identification of the rate determining process in the Hepatic Clearance of atorvastatin in a clinical cassette microdosing study
Clinical Pharmacology & Therapeutics, 2011Co-Authors: Kazuya Maeda, Kenta Yoshida, Y Ikeda, Tomoe Fujita, Y Azuma, Y Haruyama, Naoe Yamane, Yuji Kumagai, Yuichi SugiyamaAbstract:Clearance of atorvastatin occurs through Hepatic uptake by organic anion transporting polypeptides (OATPs) and subsequent metabolism by cytochrome P450 (CYP) 3A4. To demonstrate the relative importance of OATPs and CYP3A4 in the Hepatic elimination of atorvastatin in vivo, a clinical cassette microdose study was performed. A cocktail consisting of a microdose of atorvastatin along with probe substrates for OATPs (pravastatin) and CYP3A4 (midazolam) was orally administered to eight healthy volunteers. The pharmacokinetics of this cocktail was observed at baseline, after an oral dose of 600 mg rifampicin (an inhibitor of OATPs), and after an intravenous dose of 200 mg itraconazole (a CYP3A4 inhibitor). Rifampicin increased the pravastatin dose-normalized area under the plasma concentration-time curve (AUC) (4.6-fold), and itraconazole significantly increased the midazolam dose-normalized AUC (1.7-fold). The atorvastatin dose-normalized AUC increased 12-fold when coadministered with rifampicin but did not change when coadministered with itraconazole. These results indicate that Hepatic uptake via OATPs makes the dominant contribution to the Hepatic elimination of atorvastatin at a subtherapeutic microdose.
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prediction of the overall renal tubular secretion and Hepatic Clearance of anionic drugs and a renal drug drug interaction involving organic anion transporter 3 in humans by in vitro uptake experiments
Drug Metabolism and Disposition, 2011Co-Authors: Takao Watanabe, Kazuya Maeda, Hiroyuki Kusuhara, Tomoko Watanabe, Yasuyuki Debori, Tsunenori Kondo, Hideki Nakayama, Shigeru Horita, Brian W Ogilvie, Andrew ParkinsonAbstract:The present study investigated prediction of the overall renal tubular secretion and Hepatic Clearances of anionic drugs based on in vitro transport studies. The saturable uptake of eight drugs, most of which were OAT3 substrates (rosuvastatin, pravastatin, pitavastatin, valsartan, olmesartan, trichlormethiazide, p-aminohippurate, and benzylpenicillin) by freshly prepared human kidney slices underestimated the overall intrinsic Clearance of the tubular secretion; therefore, a scaling factor of 10 was required for in vitro-in vivo extrapolation. We examined the effect of gemfibrozil and its metabolites, gemfibrozil glucuronide and the carboxylic metabolite, gemfibrozil M3, on pravastatin uptake by human kidney slices. The inhibition study using human kidney slices suggests that OAT3 plays a predominant role in the renal uptake of pravastatin. Comparison of unbound concentrations and K(i) values (1.5, 9.1, and 4.0 μM, for gemfibrozil, gemfibrozil glucuronide, and gemfibrozil M3, respectively) suggests that the mechanism of the interaction is due mainly to inhibition by gemfibrozil and gemfibrozil glucuronide. Furthermore, extrapolation of saturable uptake by cryopreserved human hepatocytes predicts Clearance comparable with the observed Hepatic Clearance although fluvastatin and rosuvastatin required a scaling factor of 11 and 6.9, respectively. This study suggests that in vitro uptake assays using human kidney slices and hepatocytes provide a good prediction of the overall tubular secretion and Hepatic Clearances of anionic drugs and renal drug-drug interactions. It is also recommended that in vitro-in vivo extrapolation be performed in animals to obtain more reliable prediction.
K C Cheng - One of the best experts on this subject based on the ideXlab platform.
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use of intrinsic Clearance for prediction of human Hepatic Clearance
Expert Opinion on Drug Metabolism & Toxicology, 2010Co-Authors: Piyun Chao, Annette S Uss, K C ChengAbstract:Importance of the field: The use of intrinsic metabolic stability/Clearance and other in vitro pharmacokinetic data for the selection of drug candidates for clinical evaluation during discovery lead optimization has become one of the primary focuses of research organizations involved in new drug discovery. Using intrinsic Clearance determined from human liver microsomal preparations and/or hepatocyte to predict human Clearance has become more acceptable.Areas covered in this review: This review focuses on the current methods for determining intrinsic Clearance and scaling to predict human Hepatic Clearance, and novel physiologically-based models for improvement of human Hepatic Clearance prediction. Published microsomal metabolic stability data and in-house hepatocyte Clearance data were compared with published in vivo human Hepatic Clearance data. Various scaling models and the effect of protein binding were examined.What the reader will gain: Use of a novel microfluidic model and other physiologically-b...
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evaluation of a microfluidic based cell culture platform with primary human hepatocytes for the prediction of Hepatic Clearance in human
Biochemical Pharmacology, 2009Co-Authors: Piyun Chao, K C Cheng, Tim Maguire, Eric Novik, Martin L YarmushAbstract:Integral to the discovery of new pharmaceutical entities is the ability to predict in vivo pharmacokinetic parameters from early stage in vitro data generated prior to the onset of clinical testing. Within the pharmaceutical industry, a whole host of assay methods and mathematical models exist to predict the in vivo pharmacokinetic parameters of drug candidates. One of the most important pharmacokinetic properties of new drug candidates predicted from these methods and models is the Hepatic Clearance. Current methods, while useful, are still limited in their predictive efficacy. In order to address this issue, we have established a novel microfluidic in vitro culture system, the patented HμREL® device. The device comprises multiple compartments that are designed to be proportional to the physiological architectures and enhanced with the consideration of flow. Here we demonstrate the functionality of the liver-relevant chamber in the HμREL® device, and the feasibility of utilizing our system for predicting Hepatic Clearance. Cryopreserved human hepatocytes from a single donor were seeded within the HμREL® device to predict the in vivo Hepatic Clearance (CLH) of six marketed model compounds (carbamazepine, caffeine, timolol, sildenafil, imipramine, and buspirone). The intrinsic Clearance rates from static culture controls, as well as Clearance rates from the HμREL® device were subsequently compared to in vivo data available from the literature.
Leslie Z Benet - One of the best experts on this subject based on the ideXlab platform.
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protein binding and Hepatic Clearance re examining the discrimination between models of Hepatic Clearance with diazepam in the isolated perfused rat liver preparation
Drug Metabolism and Disposition, 2019Co-Authors: Hongjaan Wang, Leslie Z BenetAbstract:This study re-examined the Hepatic extraction for diazepam, the only drug for which isolated perfused rat liver (IPRL) studies have been reported not to be consistent with the well stirred model of organ elimination when only entering and exiting liver concentration measurements are available. First, the time dependency of diazepam equilibrium fraction unbound measurements from 4 to 24 hours was tested, reporting the continuing increases with time. The results showed that the time dependency of equilibrium protein-binding measurements for very highly bound drugs may be an issue that is not readily overcome. When examining C out/C in (F obs) measurements for diazepam when no protein is added to the incubation media, IPRL outcomes were consistent with previous reports showing marked underpredictability of in vivo Clearance from in vitro measures of elimination in the absence of protein for very highly bound drugs, which is markedly diminished in the presence of albumin. F obs for diazepam at additional low concentrations of protein that would allow discrimination of the models of Hepatic elimination produced results that were not consistent with the dispersion and parallel-tube models. Therefore, although the outcomes of this study were similar to those reported by Rowland and co-workers, when no protein is added to the perfusion media, these IPRL results for diazepam cannot be reasonably interpreted as proving that Hepatic organ elimination is model-independent or as supporting the dispersion and parallel-tube models of organ elimination. SIGNIFICANCE STATEMENT: The only drug experiments for which isolated perfusion rat liver studies do not support Hepatic Clearance being best described by the well stirred model have been carried out with diazepam at zero protein concentration. This study repeated those studies, confirming the previous results at zero protein concentration, but the addition of low protein-binding conditions capable of differentiating the various models of Hepatic elimination are more consistent with the well stirred model of Hepatic elimination. These experimental studies do not support the preference for alternate models of Hepatic elimination or the proposal that Hepatic organ Clearance is model-independent.
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Hepatic Clearance but not gut availability of erythromycin is altered in patients with end stage renal disease
Clinical Pharmacology & Therapeutics, 2010Co-Authors: Hong Sun, Lynda A Frassetto, Yong Huang, Leslie Z BenetAbstract:Nonrenal Clearance of drugs can be significantly lower in patients with end-stage renal disease (ESRD) than in those with normal renal function. Using erythromycin (ER) as a probe compound, we investigated whether this decrease in nonrenal Clearance is due to reduced Hepatic Clearance (CL(H)) and/or gut metabolism. We also examined the potential effects of the uremic toxins 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) and indoxyl sulfate (Indox) on ER disposition. Route-randomized, two-way crossover pharmacokinetic studies of ER were conducted in 12 ESRD patients and 12 healthy controls after oral (250 mg) and intravenous (125 mg) dosing with ER. In patients with ESRD, CL(H) decreased 31% relative to baseline values (0.35 +/- 0.14 l/h/kg vs. 0.51 +/- 0.13 l/h/kg, P = 0.01), with no change in steady-state volume of distribution. With oral dosing, the bioavailability of ER increased 36% in patients with ESRD, and this increase was not related to changes in gut availability. As expected, plasma levels of CMPF and Indox were significantly higher in the patients than in the healthy controls. However, no correlation was observed between CL(H) of ER and the levels of uremic toxins.
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uremic toxins inhibit Hepatic uptake of eprosartan
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Yong Huang, Lynda A Frassetto, Hideaki Okochi, Leslie Z BenetAbstract:Background Hepatic Clearance of eprosartan (Epr) is significantly decreased in patients with end stage renal disease (ESRD). Uremic toxins may directly inhibit the transporter-mediated uptake and efflux thereby reducing Hepatic Clearance of Epr, which is not metabolized by CYPs. Methods The inhibitory effects of the uremic toxins, CMPF and indoxyl sulfate, on uptake transporters (rOatp2 and hOATP-C) and the efflux transporter (P-gp) were examined using transient transfected HEK293 cells and MDR1-MDCK cells, respectively. The effects of these uremic toxins on Epr uptake were further evaluated in rat hepatocytes and hOATP-C transfected cells. Results Both CMPF and indoxyl sulfate exhibited dose-dependent inhibition of rOatp2 and hOATP-C. The IC50s of CMPF on rOatp2 and hOATP-C mediated uptake of estrone sulfate (1 μM) were 25 μM and 55 μM, respectively. Indoxyl sulfate is a weaker inhibitor of rOatp2 and hOATP-C with IC50s of 97 μM and 397 μM, respectively. Both uremic toxins had no effects on P-gp. The uptake of Epr was mainly mediated by rOatp2 in rat. At 200μM, CMPF significantly inhibited Epr uptake by 53% in rat hepatocytes. The uptake of Epr was mediated by OATP-C in human hepatocytes with a K m value of 12.5± 0.3 μM. CMPF dose-dependently inhibited Epr (5 μM) uptake by hOATP-C with an IC50 of 125.9± 1.3 μM. Conclusion Our study suggests that the inhibitory effect of CMPF may at least partially contribute to the reduced Hepatic Clearance of Epr in ESRD patients. Clinical Pharmacology & Therapeutics (2005) 77, P2–P2; doi: 10.1016/j.clpt.2004.11.012
Piyun Chao - One of the best experts on this subject based on the ideXlab platform.
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use of intrinsic Clearance for prediction of human Hepatic Clearance
Expert Opinion on Drug Metabolism & Toxicology, 2010Co-Authors: Piyun Chao, Annette S Uss, K C ChengAbstract:Importance of the field: The use of intrinsic metabolic stability/Clearance and other in vitro pharmacokinetic data for the selection of drug candidates for clinical evaluation during discovery lead optimization has become one of the primary focuses of research organizations involved in new drug discovery. Using intrinsic Clearance determined from human liver microsomal preparations and/or hepatocyte to predict human Clearance has become more acceptable.Areas covered in this review: This review focuses on the current methods for determining intrinsic Clearance and scaling to predict human Hepatic Clearance, and novel physiologically-based models for improvement of human Hepatic Clearance prediction. Published microsomal metabolic stability data and in-house hepatocyte Clearance data were compared with published in vivo human Hepatic Clearance data. Various scaling models and the effect of protein binding were examined.What the reader will gain: Use of a novel microfluidic model and other physiologically-b...
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evaluation of a microfluidic based cell culture platform with primary human hepatocytes for the prediction of Hepatic Clearance in human
Biochemical Pharmacology, 2009Co-Authors: Piyun Chao, K C Cheng, Tim Maguire, Eric Novik, Martin L YarmushAbstract:Integral to the discovery of new pharmaceutical entities is the ability to predict in vivo pharmacokinetic parameters from early stage in vitro data generated prior to the onset of clinical testing. Within the pharmaceutical industry, a whole host of assay methods and mathematical models exist to predict the in vivo pharmacokinetic parameters of drug candidates. One of the most important pharmacokinetic properties of new drug candidates predicted from these methods and models is the Hepatic Clearance. Current methods, while useful, are still limited in their predictive efficacy. In order to address this issue, we have established a novel microfluidic in vitro culture system, the patented HμREL® device. The device comprises multiple compartments that are designed to be proportional to the physiological architectures and enhanced with the consideration of flow. Here we demonstrate the functionality of the liver-relevant chamber in the HμREL® device, and the feasibility of utilizing our system for predicting Hepatic Clearance. Cryopreserved human hepatocytes from a single donor were seeded within the HμREL® device to predict the in vivo Hepatic Clearance (CLH) of six marketed model compounds (carbamazepine, caffeine, timolol, sildenafil, imipramine, and buspirone). The intrinsic Clearance rates from static culture controls, as well as Clearance rates from the HμREL® device were subsequently compared to in vivo data available from the literature.