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David J. Greenblatt - One of the best experts on this subject based on the ideXlab platform.
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mechanism of Cytochrome P450 3A inhibition by ketoconazole
Journal of Pharmacy and Pharmacology, 2011Co-Authors: David J. Greenblatt, Jerold S. Harmatz, Yanli Zhao, Karthik Venkatakrishnan, Su X Duan, Sarah J Parent, Michael H Court, Lisa L. Von MoltkeAbstract:Objectives Ketoconazole is extensively used as an index inhibitor of Cytochrome P450-3A (CYP3A) activity in vitro and in vivo, but the mechanism of ketoconazole inhibition of CYP3A still is not clearly established. Methods Inhibition of metabolite formation by ketoconazole (seven concentrations from 0.01 to 1.0 µm) was studied in human liver microsomes (n = 4) at six to seven substrate concentrations for triazolam, midazolam, and testosterone, and at two substrate concentrations for nifedipine. Key findings Analysis of multiple data points per liver sample based on a mixed competitive–noncompetitive model yielded mean inhibition constant Ki values in the range of 0.011 to 0.045 µm. Ketoconazole IC50 increased at higher substrate concentrations, thereby excluding pure noncompetitive inhibition. For triazolam, testosterone, and midazolam α-hydroxylation, mean values of α (indicating the ‘mix’ of competitive and noncompetitive inhibition) ranged from 2.1 to 6.3. However, inhibition of midazolam 4-hydroxylation was consistent with a competitive process. Determination of Ki and α based on the relation between 50% inhibitory concentration values and substrate concentration yielded similar values. Pre-incubation of ketoconazole with microsomes before addition of substrate did not enhance inhibition, whereas inhibition by troleandomycin was significantly enhanced by pre-incubation. Conclusions Ketoconazole inhibition of triazolam α- and 4-hydroxylation, midazolam α-hydroxylation, testosterone 6β-hydroxylation, and nifedipine oxidation appeared to be a mixed competitive–noncompetitive process, with the noncompetitive component being dominant but not exclusive. Quantitative estimates of Ki were in the low nanomolar range for all four substrates.
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sources of variability in ketoconazole inhibition of human Cytochrome P450 3A in vitro
Xenobiotica, 2010Co-Authors: David J. Greenblatt, Jerold S. Harmatz, Karthik Venkatakrishnan, Sarah J Parent, Lisa L. Von MoltkeAbstract:Despite the extensive use of ketoconazole as an index inhibitor of human Cytochrome P450 3A (CYP3A) isoforms in vitro, literature reports of the quantitative inhibitory potency of ketoconazole are highly variable.In 51 published studies reporting 76 values of ketoconazole inhibition constants (Ki) versus in vitro clearance of 31 different CYP3A substrates, the Ki values ranged from 0.001 µM to 25 µM. The geometric mean was 0.1 µM (90% confidence interval: 0.07 to 0.15 µM), and the median was 0.08 µM.Even for one specific substrate metabolized to one specific metabolite (midazolam α-hydroxylation), variability was still extensive (Ki range: 0.004–0.18 µM).Only about 20% of overall variability in Ki was explained by a combination of incubation, duration, and microsomal protein concentration. The remaining variation is unexplained, but could be attributable to factors such as: in vitro clearance by non-CYP3A pathways; incorrect assignment of inhibition mechanism; and variable relative content of CYP3A4 and C...
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Identification of polymorphisms in the 3'-untranslated region of the human pregnane X receptor (PXR) gene associated with variability in Cytochrome P450 3A (CYP3A) metabolism.
Xenobiotica, 2010Co-Authors: Lauren E. Oleson, David J. Greenblatt, L. L. Von Moltke, Michael H CourtAbstract:Single nucleotide polymorphisms in the 3′-untranslated region (3′UTR) of the human pregnane X receptor (PXR) gene might contribute to interindividual variability in Cytochrome P450 3A (CYP3A) activity.Genotype–phenotype associations involving PXR-3′UTR single nucleotide polymorphisms were investigated through in vitro (53 human livers from primarily White donors) and in vivo (26 mainly White or African-American volunteers) studies using midazolam 1′-hydroxylation and midazolam apparent oral clearance (CL/F), respectively, as CYP3A-specific probes.PXR-3′UTR resequencing identified twelve single nucleotide polymorphisms, including two that were novel. Although none of the single nucleotide polymorphisms evaluated were associated with altered midazolam 1′-hydroxylation in the liver bank, both rs3732359 homozygotes and rs3732360 carriers showed 80% higher (p
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identification of polymorphisms in the 3 untranslated region of the human pregnane x receptor pxr gene associated with variability in Cytochrome P450 3A cyp3A metabolism
Xenobiotica, 2010Co-Authors: Lauren E. Oleson, David J. Greenblatt, L. L. Von Moltke, Michael H CourtAbstract:Single nucleotide polymorphisms in the 3′-untranslated region (3′UTR) of the human pregnane X receptor (PXR) gene might contribute to interindividual variability in Cytochrome P450 3A (CYP3A) activity.Genotype–phenotype associations involving PXR-3′UTR single nucleotide polymorphisms were investigated through in vitro (53 human livers from primarily White donors) and in vivo (26 mainly White or African-American volunteers) studies using midazolam 1′-hydroxylation and midazolam apparent oral clearance (CL/F), respectively, as CYP3A-specific probes.PXR-3′UTR resequencing identified twelve single nucleotide polymorphisms, including two that were novel. Although none of the single nucleotide polymorphisms evaluated were associated with altered midazolam 1′-hydroxylation in the liver bank, both rs3732359 homozygotes and rs3732360 carriers showed 80% higher (p < 0.05) CL/F compared with homozygous reference individuals. These differences in CL/F were even larger (100% and 120% higher, respectively; p < 0.01) wh...
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differentiation of intestinal and hepatic Cytochrome P450 3A activity with use of midazolam as an in vivo probe effect of ketoconazole
Clinical Pharmacology & Therapeutics, 1999Co-Authors: Lisa L. Von Moltke, David J. Greenblatt, Shirley M Tsunoda, Rebecca L VelezAbstract:Background The Cytochrome P450 3A (CYP3A) isoforms are responsible for the metabolism of a majority of therapeutic compounds, and they are abundant in the intestine and liver. CYP3A activity is highly variable, causing difficulty in the therapeutic use of CYP3A substrates. A practical in vivo probe method that characterizes both intestinal and hepatic CYP3A activity would be useful. Objectives To determine the intestinal and hepatic contribution to the bioavailability of midazolam with use of the CYP3A inhibitor ketoconazole. Methods The pharmacokinetics of midazolam was assessed in nine (six men and three women) healthy individuals after single doses of 2 mg intravenous and 6 mg oral midazolam (phase I). These pharmacokinetic values were compared with those obtained after single doses of 2 mg intravenous and 6 mg oral midazolam and three doses of 200 mg oral ketoconazole (phase II). Results After ketoconazole therapy, area under the concentration versus time curve of midazolam increased 5-fold after intravenous midazolam administration (P ≤ .001) and 16-fold after oral midazolam administration (P ≤ .001). Intrinsic clearance decreased by 84% (P = .003). Total bioavailability increased from 25% to 80% (P < .001). The intestinal component of midazolam bioavailability increased to a greater extent than the hepatic component (2.3-fold [P = .003] and 1.5-fold [P ≤ .001], respectively). In the control phase, female subjects had greater midazolam clearance values than the male subjects. Conclusions Ketoconazole caused marked inhibition of CYP3A activity that was greater in the intestine than the liver. Administration of single doses of oral and intravenous midazolam with and without oral ketoconazole exemplifies a practical method for differentiating intestinal and hepatic CYP3A activity. Clinical Pharmacology & Therapeutics (1999) 66, 461–471; doi:
Roger Rahmani - One of the best experts on this subject based on the ideXlab platform.
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Role of Cytochrome P450 3A in the metabolism of mefloquine in human and animal hepatocytes.
Life Sciences, 2000Co-Authors: Frank Fontaine, G. De Sousa, Philip C. Burcham, P. Duchene, Roger RahmaniAbstract:We studied mefloquine metabolism in cells and microsomes isolated from human and animal (monkey, dog, rat) livers. In both hepatocytes and microsomes, mefloquine underwent conversion to two major metabolites, carboxymefloquine and hydroxymefloquine. In human cells and microsomes these metabolites only were formed, as already demonstrated in vivo, while in other species several unidentified metabolites were also detected. After a 48 hr incubation with human and rat hepatocytes, metabolites accounted for 55–65 % of the initial drug concentration, whereas in monkey and dog hepatocytes, mefloquine was entirely metabolized after 15 and 39 hrs, respectively. The consumption of mefloquine was less extensive in microsomes, and unchanged drug represented 60 % (monkey) to 85–100 % (human, dog, rat) of the total radioactivity after 5 hr incubations. The involvement of the Cytochrome P450 3A subfamily in mefloquine biotransformation was suggested by several lines of evidence. Firstly, mefloquine metabolism was strongly increased in hepatic microsomes from dexamethasonepretreated rats and also in human and rat hepatocytes after prior treatment with a Cytochrome P450 3A inducer. Secondly, mefloquine biotransformation in rifampycin-induced human hepatocytes was inhibited in a concentration-dependent manner by the Cytochrome P450 3A inhibitor ketoconazole and thirdly, a strong correlation was found between erythromycin-N-demethylase activity (mediated by Cytochrome P450 3A) and mefloquine metabolism in human microsomes (r = 0.81, P < 0.05, N = 13). Collectively, these findings concerning the role of Cytochrome P450 3A in mefloquine metabolism may have important in vivo consequences especially with regard to the choice of agents used in multidrug antimalarial regimens.
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involvement of human liver Cytochrome P450 3A in vinblastine metabolism drug interactions
Cancer Research, 1993Co-Authors: Xinru Zhoupan, M Placidi, Patrick Maurel, Eric Seree, X J Zhou, Yves Barra, Roger RahmaniAbstract:Abstract Vinblastine biotransformation was investigated by using a human liver microsomes library. The drug was converted into one major metabolite (M) upon incubation with the microsomes. A large interindividual variation in vinblastine metabolism was observed among the samples tested, with a 4.4 ratio between the lowest and the highest metabolic rates. The biotransformation of vinblastine followed Michaelis-Menten kinetics ( K m = 6.82 ± 0.27 µm and V max = 0.64 ± 0.06 nmol/min/mg protein). The involvement of the Cytochrome P450 3A subfamily in vinblastine metabolism was demonstrated by the following body of evidence: ( a ) the competitive inhibition of vinblastine biotransformation by Cytochrome P450 3A specific probes with K i values of 0.17, 22.5, 14.8, and 35.3 µm for ketoconazole, erythromycin, troleandomycin, and vindesine, respectively; ( b ) the immunoinhibition of vinblastine metabolism by polyclonal anti-Cytochrome P450 3A antibodies; ( c ) the highly significant correlation between the level of Cytochrome P450 3A determined by Western blots and vinblastine metabolism ( r = 0.759, P d ) the highly significant correlation between erythromycin N -demethylase activity (mediated by Cytochrome P450 3A) and vinblastine metabolism ( r = 0.83, P e ) the significant correlation between the CYP3A4 mRNA level and vinblastine metabolism ( r = 0.60, P Vinca alkaloid family) also inhibit the metabolism of vinblastine, suggesting the involvement of the Cytochrome subfamily in their respective metabolisms, other anticancer drugs currently associated with vinblastine in chemotherapy (etoposide, Adriamycin, lomustine, and teniposide) also interfere with vinblastine biotransformation. These metabolic drug interactions may alter the antitumor activity and/or toxicity of the drug during anticancer chemotherapy.
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human liver microsomal Cytochrome P450 3A isozymes mediated vindesine biotransformation metabolic drug interactions
Biochemical Pharmacology, 1993Co-Authors: Xiaojian Zhou, Xinru Zhoupan, Therese Gauthier, M Placidi, Patrick Maurel, Roger RahmaniAbstract:Vindesine biotransformation was investigated using a bank of human liver microsomes. The drug was converted into one major metabolite (M) upon incubation with the microsomes. Large inter-individual variations were observed: vindesine biotransformation rates ranged from 1.2 to 12.9 pmol/min/mg protein. Vindesine metabolic processes followed Michaelis-Menten kinetics: Km = 24.7 ± 9.4 μM, Vmax = 1.5 ± 0.8 nmol/min/mg protein. The involvement of human Cytochrome P450 3A isozymes in vindesine metabolism was demonstrated by: (1) competitive inhibition of vindesine biotransformation by compounds known to be specifically metabolized by human Cytochrome P450 3A. Apparent Ki values were 3.6, 17.9 and 19.8 μM for quinidine, troleandomycin and erythromycin, respectively; (2) immunoinhibition of vindesine metabolism by polyclonal anti-P450 3A antibody; (3) significant correlation between immunoquantified P450 3A and vindesine biotransformation (r = 0.800, P < 0.001); and (4) significant correlation between erythromycin N-demethylase activity, which was supported by P450 3A in humans, and vindesine biotransformation (r = 0.853, P < 0.001). Other vinca alkaloids also exerted an inhibitory effect on vindesine biotransformation with apparent Ki values of 3.8, 10.6 and 19.2 μM for vinblastine, vincristine and navelbine, respectively, suggesting a possible involvement of the same Cytochrome subfamily in their hepatic metabolism. Moreover, a number of anticancer drugs currently associated with the vinca alkaloids, such as teniposide, etoposide, doxorubicin, lomustine, folinic acid and mitoxantrone, significantly inhibited vindesine biotransformation.
Xinru Zhoupan - One of the best experts on this subject based on the ideXlab platform.
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involvement of human liver Cytochrome P450 3A in vinblastine metabolism drug interactions
Cancer Research, 1993Co-Authors: Xinru Zhoupan, M Placidi, Patrick Maurel, Eric Seree, X J Zhou, Yves Barra, Roger RahmaniAbstract:Abstract Vinblastine biotransformation was investigated by using a human liver microsomes library. The drug was converted into one major metabolite (M) upon incubation with the microsomes. A large interindividual variation in vinblastine metabolism was observed among the samples tested, with a 4.4 ratio between the lowest and the highest metabolic rates. The biotransformation of vinblastine followed Michaelis-Menten kinetics ( K m = 6.82 ± 0.27 µm and V max = 0.64 ± 0.06 nmol/min/mg protein). The involvement of the Cytochrome P450 3A subfamily in vinblastine metabolism was demonstrated by the following body of evidence: ( a ) the competitive inhibition of vinblastine biotransformation by Cytochrome P450 3A specific probes with K i values of 0.17, 22.5, 14.8, and 35.3 µm for ketoconazole, erythromycin, troleandomycin, and vindesine, respectively; ( b ) the immunoinhibition of vinblastine metabolism by polyclonal anti-Cytochrome P450 3A antibodies; ( c ) the highly significant correlation between the level of Cytochrome P450 3A determined by Western blots and vinblastine metabolism ( r = 0.759, P d ) the highly significant correlation between erythromycin N -demethylase activity (mediated by Cytochrome P450 3A) and vinblastine metabolism ( r = 0.83, P e ) the significant correlation between the CYP3A4 mRNA level and vinblastine metabolism ( r = 0.60, P Vinca alkaloid family) also inhibit the metabolism of vinblastine, suggesting the involvement of the Cytochrome subfamily in their respective metabolisms, other anticancer drugs currently associated with vinblastine in chemotherapy (etoposide, Adriamycin, lomustine, and teniposide) also interfere with vinblastine biotransformation. These metabolic drug interactions may alter the antitumor activity and/or toxicity of the drug during anticancer chemotherapy.
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human liver microsomal Cytochrome P450 3A isozymes mediated vindesine biotransformation metabolic drug interactions
Biochemical Pharmacology, 1993Co-Authors: Xiaojian Zhou, Xinru Zhoupan, Therese Gauthier, M Placidi, Patrick Maurel, Roger RahmaniAbstract:Vindesine biotransformation was investigated using a bank of human liver microsomes. The drug was converted into one major metabolite (M) upon incubation with the microsomes. Large inter-individual variations were observed: vindesine biotransformation rates ranged from 1.2 to 12.9 pmol/min/mg protein. Vindesine metabolic processes followed Michaelis-Menten kinetics: Km = 24.7 ± 9.4 μM, Vmax = 1.5 ± 0.8 nmol/min/mg protein. The involvement of human Cytochrome P450 3A isozymes in vindesine metabolism was demonstrated by: (1) competitive inhibition of vindesine biotransformation by compounds known to be specifically metabolized by human Cytochrome P450 3A. Apparent Ki values were 3.6, 17.9 and 19.8 μM for quinidine, troleandomycin and erythromycin, respectively; (2) immunoinhibition of vindesine metabolism by polyclonal anti-P450 3A antibody; (3) significant correlation between immunoquantified P450 3A and vindesine biotransformation (r = 0.800, P < 0.001); and (4) significant correlation between erythromycin N-demethylase activity, which was supported by P450 3A in humans, and vindesine biotransformation (r = 0.853, P < 0.001). Other vinca alkaloids also exerted an inhibitory effect on vindesine biotransformation with apparent Ki values of 3.8, 10.6 and 19.2 μM for vinblastine, vincristine and navelbine, respectively, suggesting a possible involvement of the same Cytochrome subfamily in their hepatic metabolism. Moreover, a number of anticancer drugs currently associated with the vinca alkaloids, such as teniposide, etoposide, doxorubicin, lomustine, folinic acid and mitoxantrone, significantly inhibited vindesine biotransformation.
Lisa L. Von Moltke - One of the best experts on this subject based on the ideXlab platform.
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mechanism of Cytochrome P450 3A inhibition by ketoconazole
Journal of Pharmacy and Pharmacology, 2011Co-Authors: David J. Greenblatt, Jerold S. Harmatz, Yanli Zhao, Karthik Venkatakrishnan, Su X Duan, Sarah J Parent, Michael H Court, Lisa L. Von MoltkeAbstract:Objectives Ketoconazole is extensively used as an index inhibitor of Cytochrome P450-3A (CYP3A) activity in vitro and in vivo, but the mechanism of ketoconazole inhibition of CYP3A still is not clearly established. Methods Inhibition of metabolite formation by ketoconazole (seven concentrations from 0.01 to 1.0 µm) was studied in human liver microsomes (n = 4) at six to seven substrate concentrations for triazolam, midazolam, and testosterone, and at two substrate concentrations for nifedipine. Key findings Analysis of multiple data points per liver sample based on a mixed competitive–noncompetitive model yielded mean inhibition constant Ki values in the range of 0.011 to 0.045 µm. Ketoconazole IC50 increased at higher substrate concentrations, thereby excluding pure noncompetitive inhibition. For triazolam, testosterone, and midazolam α-hydroxylation, mean values of α (indicating the ‘mix’ of competitive and noncompetitive inhibition) ranged from 2.1 to 6.3. However, inhibition of midazolam 4-hydroxylation was consistent with a competitive process. Determination of Ki and α based on the relation between 50% inhibitory concentration values and substrate concentration yielded similar values. Pre-incubation of ketoconazole with microsomes before addition of substrate did not enhance inhibition, whereas inhibition by troleandomycin was significantly enhanced by pre-incubation. Conclusions Ketoconazole inhibition of triazolam α- and 4-hydroxylation, midazolam α-hydroxylation, testosterone 6β-hydroxylation, and nifedipine oxidation appeared to be a mixed competitive–noncompetitive process, with the noncompetitive component being dominant but not exclusive. Quantitative estimates of Ki were in the low nanomolar range for all four substrates.
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sources of variability in ketoconazole inhibition of human Cytochrome P450 3A in vitro
Xenobiotica, 2010Co-Authors: David J. Greenblatt, Jerold S. Harmatz, Karthik Venkatakrishnan, Sarah J Parent, Lisa L. Von MoltkeAbstract:Despite the extensive use of ketoconazole as an index inhibitor of human Cytochrome P450 3A (CYP3A) isoforms in vitro, literature reports of the quantitative inhibitory potency of ketoconazole are highly variable.In 51 published studies reporting 76 values of ketoconazole inhibition constants (Ki) versus in vitro clearance of 31 different CYP3A substrates, the Ki values ranged from 0.001 µM to 25 µM. The geometric mean was 0.1 µM (90% confidence interval: 0.07 to 0.15 µM), and the median was 0.08 µM.Even for one specific substrate metabolized to one specific metabolite (midazolam α-hydroxylation), variability was still extensive (Ki range: 0.004–0.18 µM).Only about 20% of overall variability in Ki was explained by a combination of incubation, duration, and microsomal protein concentration. The remaining variation is unexplained, but could be attributable to factors such as: in vitro clearance by non-CYP3A pathways; incorrect assignment of inhibition mechanism; and variable relative content of CYP3A4 and C...
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differentiation of intestinal and hepatic Cytochrome P450 3A activity with use of midazolam as an in vivo probe effect of ketoconazole
Clinical Pharmacology & Therapeutics, 1999Co-Authors: Lisa L. Von Moltke, David J. Greenblatt, Shirley M Tsunoda, Rebecca L VelezAbstract:Background The Cytochrome P450 3A (CYP3A) isoforms are responsible for the metabolism of a majority of therapeutic compounds, and they are abundant in the intestine and liver. CYP3A activity is highly variable, causing difficulty in the therapeutic use of CYP3A substrates. A practical in vivo probe method that characterizes both intestinal and hepatic CYP3A activity would be useful. Objectives To determine the intestinal and hepatic contribution to the bioavailability of midazolam with use of the CYP3A inhibitor ketoconazole. Methods The pharmacokinetics of midazolam was assessed in nine (six men and three women) healthy individuals after single doses of 2 mg intravenous and 6 mg oral midazolam (phase I). These pharmacokinetic values were compared with those obtained after single doses of 2 mg intravenous and 6 mg oral midazolam and three doses of 200 mg oral ketoconazole (phase II). Results After ketoconazole therapy, area under the concentration versus time curve of midazolam increased 5-fold after intravenous midazolam administration (P ≤ .001) and 16-fold after oral midazolam administration (P ≤ .001). Intrinsic clearance decreased by 84% (P = .003). Total bioavailability increased from 25% to 80% (P < .001). The intestinal component of midazolam bioavailability increased to a greater extent than the hepatic component (2.3-fold [P = .003] and 1.5-fold [P ≤ .001], respectively). In the control phase, female subjects had greater midazolam clearance values than the male subjects. Conclusions Ketoconazole caused marked inhibition of CYP3A activity that was greater in the intestine than the liver. Administration of single doses of oral and intravenous midazolam with and without oral ketoconazole exemplifies a practical method for differentiating intestinal and hepatic CYP3A activity. Clinical Pharmacology & Therapeutics (1999) 66, 461–471; doi:
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Unchanged Cytochrome P450 3A (CYP3A) expression and metabolism of midazolam, triazolam, and dexamethasone in mdr(−/−) mouse liver microsomes
Biochemical Pharmacology, 1999Co-Authors: Michael D. Perloff, Lisa L. Von Moltke, Monette M. Cotreau, David J. GreenblattAbstract:Abstract P-Glycoprotein (P-gp) and Cytochrome P450 3A (CYP3A) share common substrates and expression properties, but the relationship of mdr1 deficiency to CYP3A-mediated metabolism and protein expression is not established. The in vitro kinetic parameters of CYP3A-mediated metabolism of midazolam (MDZ), triazolam (TRZ), and dexamethasone (DEX) were studied in liver microsomes from three mdr1a(−/−) mice, one mdr1a/b(−/−) mouse, and mdr1a/b(+/+) controls. The kinetic profiles of CYP3A-mediated MDZ 4-hydroxylation were not significantly different between mdr1 -deficient animals and controls. Overall mean (± SEM, N = 8) values were: V max , 0.74 ± 0.05 nmol/min/mg protein; K m , 28.2 ± 2.7 μM; and estimated intrinsic clearance, 0.026 ± 0.003 mL/min/mg protein. Likewise, rates of formation of α-OH- and 4-OH-TRZ (from 500 μM TRZ), and of DEX metabolites sensitive to ketoconazole inhibition, M1 and M5 (from 20 μM DEX), did not differ between mdr1- deficient and control animals. Immunoquantified microsomal CYP3A protein levels in mdr1a(−/−), mdr1a/b(−/−), and mdr1a/b(+/+) mice were not different, with overall mean immunoreactive protein levels of 2.68 ± 0.09 pmol/μg protein. Although CYP3A and P-gp share aspects of activity and expression, disruption of the mdr1 genes does not affect CYP3A-mediated metabolism or protein expression in the mouse.
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Venlafaxine and metabolites are very weak inhibitors of human Cytochrome P450-3A isoforms
Biological Psychiatry, 1997Co-Authors: Lisa L. Von Moltke, Su Xiang Duan, David J. Greenblatt, Steven M. Fogelman, Jürgen Schmider, Jerold S. Harmatz, Richard I. ShaderAbstract:Cytochrome P450-3A isoforms mediate the metabolism of a large number of drugs used in clinical practice (Harvey and Preskom 1996; Ketter et al 1995; yon Moltke et al 1995b). The class of selective serotonin reuptake inhibitor (SSRI) antidepressants has the capacity to inhibit reversibly the activity of human Cytochrome P450-3A isoforms, accounting for a number of pharmacokinetic drug interactions. Cotreatment with fluoxetine, for example, impairs metabolic clearance and/or elevates steadystate plasma concentrations of P450-3A substrates such as diazepam, alprazolam, amitriptyline, imipramine, and carbamazepine (Greenblatt et al in press). The inhibitory activity of fluoxetine appears to be attributable mainly to its metabolite, norfluoxetine. Fluvoxamine also is a P450-3A inhibitor, causing pharmacokinetic interactions with alprazolam (Fleishaker and Hulst 1994), diazepam (Perucca et al 1994), and haloperidol (Daniel et al 1994). The antidepressant nefazodone, which produces presynaptic serotonin and norepinephrine reuptake inhibition and postsynaptic serotonin (5-HT) 2 receptor blockade (Ellingrod and Perry 1995), is a reasonably potent 3A inhibitor (von Moltke et al 1996b), significantly elevating plasma concentrations of alprazolam (Greene et al 1995) and triazolam (Barbhaiya et al 1995) when coadministered with these drugs. The antidepressant venlafaxine (VF) acts by blocking reuptake
Xiaojian Zhou - One of the best experts on this subject based on the ideXlab platform.
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human liver microsomal Cytochrome P450 3A isozymes mediated vindesine biotransformation metabolic drug interactions
Biochemical Pharmacology, 1993Co-Authors: Xiaojian Zhou, Xinru Zhoupan, Therese Gauthier, M Placidi, Patrick Maurel, Roger RahmaniAbstract:Vindesine biotransformation was investigated using a bank of human liver microsomes. The drug was converted into one major metabolite (M) upon incubation with the microsomes. Large inter-individual variations were observed: vindesine biotransformation rates ranged from 1.2 to 12.9 pmol/min/mg protein. Vindesine metabolic processes followed Michaelis-Menten kinetics: Km = 24.7 ± 9.4 μM, Vmax = 1.5 ± 0.8 nmol/min/mg protein. The involvement of human Cytochrome P450 3A isozymes in vindesine metabolism was demonstrated by: (1) competitive inhibition of vindesine biotransformation by compounds known to be specifically metabolized by human Cytochrome P450 3A. Apparent Ki values were 3.6, 17.9 and 19.8 μM for quinidine, troleandomycin and erythromycin, respectively; (2) immunoinhibition of vindesine metabolism by polyclonal anti-P450 3A antibody; (3) significant correlation between immunoquantified P450 3A and vindesine biotransformation (r = 0.800, P < 0.001); and (4) significant correlation between erythromycin N-demethylase activity, which was supported by P450 3A in humans, and vindesine biotransformation (r = 0.853, P < 0.001). Other vinca alkaloids also exerted an inhibitory effect on vindesine biotransformation with apparent Ki values of 3.8, 10.6 and 19.2 μM for vinblastine, vincristine and navelbine, respectively, suggesting a possible involvement of the same Cytochrome subfamily in their hepatic metabolism. Moreover, a number of anticancer drugs currently associated with the vinca alkaloids, such as teniposide, etoposide, doxorubicin, lomustine, folinic acid and mitoxantrone, significantly inhibited vindesine biotransformation.
