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Paul B Watkins - One of the best experts on this subject based on the ideXlab platform.
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Variation in Oral Clearance of saquinavir is predicted by CYP3A5*1 genotype but not by enterocyte content of cytochrome P450 3A5.
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Stephane Mouly, Chris Matheny, Mary F Paine, Glenn Smith, Jatinder K. Lamba, Vishal Lamba, Susan N. Pusek, Erin G. Schuetz, Paul W. Stewart, Paul B WatkinsAbstract:Objective Saquinavir, a widely prescribed human immunodeficiency virus 1 protease inhibitor, has a low and variable Oral bioavailability that has been attributed to extensive first-pass extraction mediated by hepatic or intestinal cytochrome P450 (CYP) 3A4 and intestinal P-glycoprotein (P-gp). The polymorphic CYP3A5 has also been shown to influence the saquinavir metabolite/parent urinary ratio, suggesting a role for CYP3A5. Methods Twenty healthy subjects received a single Oral dose of saquinavir (600 mg) with water (control) and, on a separate occasion, with Seville orange juice (a selective intestinal CYP3A4/5 inhibitor). Hepatic CYP3A4 activity was evaluated by use of the erythromycin breath test. Duodenal biopsy specimens were used to assess relative intestinal CYP3A4 and CYP3A5 protein contents. Relative P-gp content was also assessed in the biopsy specimens and in lymphocytes. Genetic polymorphisms in MDR1 (in exon 21 and 26), CYP3A5 (*1 and *3), and CYP3A4*1B were identified by direct sequencing. Saquinavir plasma concentrations were measured by tandem liquid chromatography–mass spectrometry. Pharmacokinetic parameter estimates (maximum concentration, time to reach maximum concentration, area under the concentration-time curve, apparent Oral Clearance [CL/F]) were computed by standard noncompartmental methods. Stepwise multiple regression analysis was used to identify the hepatic or intestinal variables that predicted variation in saquinavir pharmacokinetic measures. Results Baseline saquinavir CL/F was not correlated with liver CYP3A4 activity (the erythromycin breath test result), intestinal CYP3A4 content, or intestinal P-gp content (r2 = 0.08, 0.08, and 0.007, respectively; P > .2). MDR1 genotype and lymphocyte P-gp content were also not predictive. Among the 6 subjects expressing intestinal CYP3A5, the mean saquinavir CL/F was almost twice as high as for the 14 nonexpressors (36.7 L/h [95% confidence interval (CI), 18.7–54.6 L/h] and 19.3 L/h [95% CI, 11.2–27.4 L/h], respectively; P = .03). However, among the 6 CYP3A5 expressors, there was an unexpected negative correlation between CL/F and intestinal CYP3A5 content (r2 = 0.58, P = .05). Seville orange juice decreased the mean CL/F in all 20 subjects from 24.5 L/h (95% CI, 16.7–32.3 L/h) to 14.7 L/h (95% CI, 8.4–20.6 L/h) (P = .05). The effect size did not appear to be influenced by CYP3A5 expression. Conclusions The CYP3A5*1 genotype is associated with increased saquinavir CL/F. This does not appear to reflect intestinal CYP3A5 expression and presumably reflects the contribution of hepatic CYP3A5. The interaction with Seville orange juice in subjects not expressing CYP3A5 supports a role for intestinal CYP3A4. However, the modest nature of the interaction, combined with the inability to detect a correlation between CL/F and CYP3A4 enterocyte content, supports our recent in vitro work suggesting a smaller contribution of intestinal CYP3A4 than has been assumed. Clinical Pharmacology & Therapeutics (2005) 78, 605–618; doi: 10.1016/j.clpt.2005.08.014
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caffeine based measures of cyp1a2 activity correlate with Oral Clearance of tacrine in patients with alzheimer s disease
British Journal of Clinical Pharmacology, 2002Co-Authors: Robert J Fontana, Tina M Devries, Thomas F Woolf, Margaret J Knapp, A S Brown, Laurence S Kaminsky, Bing Kuo Tang, Norman L Foster, Richard R Brown, Paul B WatkinsAbstract:Aims To study the potential utility of caffeine based probes of CYP1A2 enzyme activity in predicting the pharmokinetics of tacrine in patients with Alzheimer's disease. Methods The pharmokinetics of a single 40 mg Oral dose of tacrine were measured in 19 patients with Alzheimer's disease. Each patient also received 2 mg kg−1 [13C-3-methyl] caffeine Orally and had breath and urine samples collected. Results Tacrine Oral Clearance (CL F−1 kg−1 ), which varied 15-fold among the patients, correlated significantly with the 2 h total production of 13CO2 in breath (r=0.56, P=0.01), and with each of two commonly used urinary caffeine metabolite ratios: the raxanthine/caffeine ratio’ (1,7X+1, 7U)/1,3,7X) (r=0.76, P=0.0002) and the ‘caffeine metabolic ratio’ (AFMU+1X+1U)/1, 7U)(r=0.76, P=0.0001). Conclusions These observations support a central role for CYP1A2 in the in vivo disposition of tacrine and the potential for drug interactions when tacrine treated patients receive known inducers or inhibitors of this enzyme. The magnitude of the correlations we observed, however, are probably not suffcient to be clinically useful in individualizing tacrine therapy.
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erythromycin breath test predicts Oral Clearance of cyclosporine in kidney transplant recipients
Clinical Pharmacology & Therapeutics, 1992Co-Authors: Kim D Turgeon, Daniel P Normolle, Alan B Leichtman, Thomas M Annesley, David E Smith, Paul B WatkinsAbstract:It has been shown recently that cyclosporine is largely metabolized by P450IIIA (CYP3A), an enzyme whose catalytic activity varies significantly among patients. To determine whether heterogeneity in P450IIIA activity contributes to interpatient differences in cyclosporine dosing requirements, the Oral pharmacokinetics of the drug were determined in 20 stable kidney transplant recipients. P450IIIA activity was then measured in each patient by use of the erythromycin breath test. In the 16 patients who were at steady state, the logarithm of the apparent Oral Clearance of cyclosporine correlated significantly with the rate of 14CO2 exhaled in breath after intravenous administration of [14C N-methyl] erythromycin (r = 0.55, p = 0.03). No significant correlations existed between apparent Oral Clearance and age, high-density lipoprotein cholesterol or low-density lipoprotein cholesterol, or hematocrit in these patients. We conclude that heterogeneity in P450IIIA activity significantly contributes to interpatient differences in dosing requirements of cyclosporine in kidney transplant patients. Clinical Pharmacology and Therapeutics (1992) 52, 471–478; doi:10.1038/clpt.1992.174
Jacques Turgeon - One of the best experts on this subject based on the ideXlab platform.
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impact of gsta1 polymorphisms on busulfan Oral Clearance in adult patients undergoing hematopoietic stem cell transplantation
Pharmaceutics, 2019Co-Authors: Veronique Michaud, My Tran, Benoit Pronovost, Philippe Bouchard, Sarah Bilodeau, Karine Alain, Barbara Vadnais, Martin Franco, Francois Belanger, Jacques TurgeonAbstract:Background: Busulfan pharmacokinetics exhibit large inter-subject variability. Our objective was to evaluate the influence of glutathione S-transferase A1 (GSTA1) gene variants on busulfan Oral Clearance (CLo) in a population of patients undergoing hematopoietic stem cell transplantation. Methods: This is a quasi-experimental retrospective study in adult patients (n = 87 included in the final analyses) receiving Oral busulfan. Pharmacokinetics data (area under the plasma concentration-time curve (AUC) determined from 10 blood samples) were retrieved from patients’ files and GSTA1 *A and *B allele polymorphisms determined from banked DNA samples. Three different limited sampling methods (LSM) using four blood samples were also compared. Results: Carriers of GSTA1*B exhibited lower busulfan CLo than patients with an *A/*A genotype (p < 0.002): Busulfan CLo was 166 ± 31, 187 ± 37 vs. 207 ± 47 mL/min for GSTA1*B/*B, *A/*B and *A/*A genotypes, respectively. Similar results were obtained with the tested LSMs. Using the standard AUC method, distribution of patients above the therapeutic range after the first dose was 29% for GSTA1*A/*A, 50% for *A/*B, and 65% for *B/*B. The LSMs correctly identified ≥91% of patients with an AUC above the therapeutic range. The misclassified patients had a mean difference less than 5% in their AUCs. Conclusion: Patients carrying GSTA1 loss of function *B allele were at increased risk of overdosing on their initial busulfan Oral dose. Genetic polymorphisms associated with GSTA1 explain a significant part of busulfan CLo variability which could be captured by LSM strategies.
Stephane Mouly - One of the best experts on this subject based on the ideXlab platform.
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variation in Oral Clearance of saquinavir is predicted by cyp3a5 1 genotype but not by enterocyte content of cytochrome p450 3a5
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Stephane Mouly, Chris Matheny, Mary F Paine, Glenn SmithAbstract:Objective Saquinavir, a widely prescribed human immunodeficiency virus 1 protease inhibitor, has a low and variable Oral bioavailability that has been attributed to extensive first-pass extraction mediated by hepatic or intestinal cytochrome P450 (CYP) 3A4 and intestinal P-glycoprotein (P-gp). The polymorphic CYP3A5 has also been shown to influence the saquinavir metabolite/parent urinary ratio, suggesting a role for CYP3A5. Methods Twenty healthy subjects received a single Oral dose of saquinavir (600 mg) with water (control) and, on a separate occasion, with Seville orange juice (a selective intestinal CYP3A4/5 inhibitor). Hepatic CYP3A4 activity was evaluated by use of the erythromycin breath test. Duodenal biopsy specimens were used to assess relative intestinal CYP3A4 and CYP3A5 protein contents. Relative P-gp content was also assessed in the biopsy specimens and in lymphocytes. Genetic polymorphisms in MDR1 (in exon 21 and 26), CYP3A5 (*1 and *3), and CYP3A4*1B were identified by direct sequencing. Saquinavir plasma concentrations were measured by tandem liquid chromatography–mass spectrometry. Pharmacokinetic parameter estimates (maximum concentration, time to reach maximum concentration, area under the concentration-time curve, apparent Oral Clearance [CL/F]) were computed by standard noncompartmental methods. Stepwise multiple regression analysis was used to identify the hepatic or intestinal variables that predicted variation in saquinavir pharmacokinetic measures. Results Baseline saquinavir CL/F was not correlated with liver CYP3A4 activity (the erythromycin breath test result), intestinal CYP3A4 content, or intestinal P-gp content (r2 = 0.08, 0.08, and 0.007, respectively; P > .2). MDR1 genotype and lymphocyte P-gp content were also not predictive. Among the 6 subjects expressing intestinal CYP3A5, the mean saquinavir CL/F was almost twice as high as for the 14 nonexpressors (36.7 L/h [95% confidence interval (CI), 18.7–54.6 L/h] and 19.3 L/h [95% CI, 11.2–27.4 L/h], respectively; P = .03). However, among the 6 CYP3A5 expressors, there was an unexpected negative correlation between CL/F and intestinal CYP3A5 content (r2 = 0.58, P = .05). Seville orange juice decreased the mean CL/F in all 20 subjects from 24.5 L/h (95% CI, 16.7–32.3 L/h) to 14.7 L/h (95% CI, 8.4–20.6 L/h) (P = .05). The effect size did not appear to be influenced by CYP3A5 expression. Conclusions The CYP3A5*1 genotype is associated with increased saquinavir CL/F. This does not appear to reflect intestinal CYP3A5 expression and presumably reflects the contribution of hepatic CYP3A5. The interaction with Seville orange juice in subjects not expressing CYP3A5 supports a role for intestinal CYP3A4. However, the modest nature of the interaction, combined with the inability to detect a correlation between CL/F and CYP3A4 enterocyte content, supports our recent in vitro work suggesting a smaller contribution of intestinal CYP3A4 than has been assumed. Clinical Pharmacology & Therapeutics (2005) 78, 605–618; doi: 10.1016/j.clpt.2005.08.014
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Variation in Oral Clearance of saquinavir is predicted by CYP3A5*1 genotype but not by enterocyte content of cytochrome P450 3A5.
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Stephane Mouly, Chris Matheny, Mary F Paine, Glenn Smith, Jatinder K. Lamba, Vishal Lamba, Susan N. Pusek, Erin G. Schuetz, Paul W. Stewart, Paul B WatkinsAbstract:Objective Saquinavir, a widely prescribed human immunodeficiency virus 1 protease inhibitor, has a low and variable Oral bioavailability that has been attributed to extensive first-pass extraction mediated by hepatic or intestinal cytochrome P450 (CYP) 3A4 and intestinal P-glycoprotein (P-gp). The polymorphic CYP3A5 has also been shown to influence the saquinavir metabolite/parent urinary ratio, suggesting a role for CYP3A5. Methods Twenty healthy subjects received a single Oral dose of saquinavir (600 mg) with water (control) and, on a separate occasion, with Seville orange juice (a selective intestinal CYP3A4/5 inhibitor). Hepatic CYP3A4 activity was evaluated by use of the erythromycin breath test. Duodenal biopsy specimens were used to assess relative intestinal CYP3A4 and CYP3A5 protein contents. Relative P-gp content was also assessed in the biopsy specimens and in lymphocytes. Genetic polymorphisms in MDR1 (in exon 21 and 26), CYP3A5 (*1 and *3), and CYP3A4*1B were identified by direct sequencing. Saquinavir plasma concentrations were measured by tandem liquid chromatography–mass spectrometry. Pharmacokinetic parameter estimates (maximum concentration, time to reach maximum concentration, area under the concentration-time curve, apparent Oral Clearance [CL/F]) were computed by standard noncompartmental methods. Stepwise multiple regression analysis was used to identify the hepatic or intestinal variables that predicted variation in saquinavir pharmacokinetic measures. Results Baseline saquinavir CL/F was not correlated with liver CYP3A4 activity (the erythromycin breath test result), intestinal CYP3A4 content, or intestinal P-gp content (r2 = 0.08, 0.08, and 0.007, respectively; P > .2). MDR1 genotype and lymphocyte P-gp content were also not predictive. Among the 6 subjects expressing intestinal CYP3A5, the mean saquinavir CL/F was almost twice as high as for the 14 nonexpressors (36.7 L/h [95% confidence interval (CI), 18.7–54.6 L/h] and 19.3 L/h [95% CI, 11.2–27.4 L/h], respectively; P = .03). However, among the 6 CYP3A5 expressors, there was an unexpected negative correlation between CL/F and intestinal CYP3A5 content (r2 = 0.58, P = .05). Seville orange juice decreased the mean CL/F in all 20 subjects from 24.5 L/h (95% CI, 16.7–32.3 L/h) to 14.7 L/h (95% CI, 8.4–20.6 L/h) (P = .05). The effect size did not appear to be influenced by CYP3A5 expression. Conclusions The CYP3A5*1 genotype is associated with increased saquinavir CL/F. This does not appear to reflect intestinal CYP3A5 expression and presumably reflects the contribution of hepatic CYP3A5. The interaction with Seville orange juice in subjects not expressing CYP3A5 supports a role for intestinal CYP3A4. However, the modest nature of the interaction, combined with the inability to detect a correlation between CL/F and CYP3A4 enterocyte content, supports our recent in vitro work suggesting a smaller contribution of intestinal CYP3A4 than has been assumed. Clinical Pharmacology & Therapeutics (2005) 78, 605–618; doi: 10.1016/j.clpt.2005.08.014
Tina M Devries - One of the best experts on this subject based on the ideXlab platform.
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caffeine based measures of cyp1a2 activity correlate with Oral Clearance of tacrine in patients with alzheimer s disease
British Journal of Clinical Pharmacology, 2002Co-Authors: Robert J Fontana, Tina M Devries, Thomas F Woolf, Margaret J Knapp, A S Brown, Laurence S Kaminsky, Bing Kuo Tang, Norman L Foster, Richard R Brown, Paul B WatkinsAbstract:Aims To study the potential utility of caffeine based probes of CYP1A2 enzyme activity in predicting the pharmokinetics of tacrine in patients with Alzheimer's disease. Methods The pharmokinetics of a single 40 mg Oral dose of tacrine were measured in 19 patients with Alzheimer's disease. Each patient also received 2 mg kg−1 [13C-3-methyl] caffeine Orally and had breath and urine samples collected. Results Tacrine Oral Clearance (CL F−1 kg−1 ), which varied 15-fold among the patients, correlated significantly with the 2 h total production of 13CO2 in breath (r=0.56, P=0.01), and with each of two commonly used urinary caffeine metabolite ratios: the raxanthine/caffeine ratio’ (1,7X+1, 7U)/1,3,7X) (r=0.76, P=0.0002) and the ‘caffeine metabolic ratio’ (AFMU+1X+1U)/1, 7U)(r=0.76, P=0.0001). Conclusions These observations support a central role for CYP1A2 in the in vivo disposition of tacrine and the potential for drug interactions when tacrine treated patients receive known inducers or inhibitors of this enzyme. The magnitude of the correlations we observed, however, are probably not suffcient to be clinically useful in individualizing tacrine therapy.
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inhibition of tacrine Oral Clearance by cimetidine
Clinical Pharmacology & Therapeutics, 1996Co-Authors: Thomas S Forgue, Phillip A Reece, And Allen J Sedman, Tina M DevriesAbstract:Plasma tacrine, 1-hydroxytacrine, 2-hydroxytacrine, and 4-hydroxytacrine concentrations were measured in 12 healthy elderly subjects in this nonblinded two-period study to assess the effect of multiple doses of cimetidine on single-dose tacrine pharmacokinetics. Subjects received 40 mg tacrine (Cognex) alone and during multiple-dose cimetidine (300 mg four times a day) administration. Overall, tacrine and cimetidine were well tolerated by healthy elderly subjects. After coadministration of cimetidine with tacrine, plasma tacrine concentrations were approximately one-third higher than values after administration of tacrine alone; metabolite concentrations were also higher. Mean tacrine Oral Clearance was reduced by 30%; however, mean absorption rate and elimination half-life values were not affected by cimetidine. It was concluded that cimetidine inhibits first-pass hepatic extraction of tacrine by cytochrome P450 enzymes but has little effect on systemic drug Clearance. Clinical considerations may dictate a reduction in tacrine dosage when tacrine is coadministered with cimetidine. Clinical Pharmacology & Therapeutics (1996) 59, 444–449; doi:
Veronique Michaud - One of the best experts on this subject based on the ideXlab platform.
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impact of gsta1 polymorphisms on busulfan Oral Clearance in adult patients undergoing hematopoietic stem cell transplantation
Pharmaceutics, 2019Co-Authors: Veronique Michaud, My Tran, Benoit Pronovost, Philippe Bouchard, Sarah Bilodeau, Karine Alain, Barbara Vadnais, Martin Franco, Francois Belanger, Jacques TurgeonAbstract:Background: Busulfan pharmacokinetics exhibit large inter-subject variability. Our objective was to evaluate the influence of glutathione S-transferase A1 (GSTA1) gene variants on busulfan Oral Clearance (CLo) in a population of patients undergoing hematopoietic stem cell transplantation. Methods: This is a quasi-experimental retrospective study in adult patients (n = 87 included in the final analyses) receiving Oral busulfan. Pharmacokinetics data (area under the plasma concentration-time curve (AUC) determined from 10 blood samples) were retrieved from patients’ files and GSTA1 *A and *B allele polymorphisms determined from banked DNA samples. Three different limited sampling methods (LSM) using four blood samples were also compared. Results: Carriers of GSTA1*B exhibited lower busulfan CLo than patients with an *A/*A genotype (p < 0.002): Busulfan CLo was 166 ± 31, 187 ± 37 vs. 207 ± 47 mL/min for GSTA1*B/*B, *A/*B and *A/*A genotypes, respectively. Similar results were obtained with the tested LSMs. Using the standard AUC method, distribution of patients above the therapeutic range after the first dose was 29% for GSTA1*A/*A, 50% for *A/*B, and 65% for *B/*B. The LSMs correctly identified ≥91% of patients with an AUC above the therapeutic range. The misclassified patients had a mean difference less than 5% in their AUCs. Conclusion: Patients carrying GSTA1 loss of function *B allele were at increased risk of overdosing on their initial busulfan Oral dose. Genetic polymorphisms associated with GSTA1 explain a significant part of busulfan CLo variability which could be captured by LSM strategies.