Rifampin enhances cytochrome P450 (CYP) 2B6-mediated efavirenz 8-hydroxylation in healthy volunteers

The effect of rifampin on the in vivo metabolism of the antiretroviral drug efavirenz was evaluated in healthy volunteers. In a cross-over placebo control trial, healthy subjects (n = 20) were administered a single 600 mg oral dose of efavirenz after pretreatment with placebo or rifampin (600 mg/day for 10 days). Plasma and urine concentrations of efavirenz, 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz were measured by LC-MS/MS. Compared to placebo treatment, rifampin increased the oral clearance (by ∼2.5-fold) and decreased maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-∞) of efavirenz (by ∼1.6- and ∼2.5-fold respectively) (p < 0.001). Rifampin treatment substantially increased the Cmax and AUC0-12h of 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz, metabolic ratio (AUC0-72h of metabolites to AUC0-72h efavirenz) and the amount of metabolites excreted in urine (Ae0-12hr) (all, p < 0.01). Female subjects had longer elimination half-life (1.6-2.2-fold) and larger weight-adjusted distribution volume (1.6-1.9-fold) of efavirenz than male subjects (p < 0.05) in placebo and rifampin treated groups respectively. In conclusion, rifampin enhances CYP2B6-mediated efavirenz 8-hydroxylation in vivo. The metabolism of a single oral dose of efavirenz may be a suitable in vivo marker of CYP2B6 activity to evaluate induction drug interactions involving this enzyme

Rapid Identification of the Hepatic Cytochrome P450 2C19 Activity Using a Novel and Noninvasive [ 13 C]Pantoprazole Breath Test

ABSTRACT We tested the hypothesis that the stable isotope [ 13 C]pantoprazole is O-demethylated by cytochrome P450 CYP2C19 and that the 13 CO 2 produced and exhaled in breath as a result can serve as a safe, rapid, and noninvasive phenotyping marker of CYP2C19 activity in vivo. Healthy volunteers who had been genotyped for the CYP2C19*2, CYP2C19*3, and CYP2C19*17 alleles were administered a single oral dose of [ 13 C]pantoprazole sodium-sesquihydrate (100 mg) with 2.1 g of sodium bicarbonate. Exhaled 13 CO 2 and 12 CO 2 were measured by IR spectroscopy before (baseline) and 2.5 to 120 min after dosing. Ratios of 13 CO 2 / 12 CO 2 after [ 13 C]pantoprazole relative to 13 CO 2 / 12 CO 2 at baseline were expressed as change over baseline (DOB). Maximal DOB, DOB 15 to DOB 120 , and area under the DOB versus time curve (AUC 0 -120 and AUC 0 -ϱ ) were significantly different among three genotype groups (CYP2C19*1/ *1, n ϭ 10; CYP2C19*1/*2 or CYP2C19*1/*3, n ϭ 10; and CYP2C19*2/*2, n ϭ 5) with predicted extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs) of CYP2C19, respectively (Kruskal-Wallis test, p Ͻ 0.01); linear regression analysis indicated a gene-dose effect relationship (r 2 ranged between 0.236 and 0.522; all p Ͻ 0.05). These breath test indices were significantly lower in PMs than IMs (p Ͻ 0.05) or EMs (p Ͻ 0.01) of CYP2C19. [ 13 C]Pantoprazole plasma exposure showed significant inverse correlation with breath test indices in the respective subjects (Pearson r ϭ Ϫ0.74; p ϭ 0.038). These feasibility data suggest that the [ 13 C]pantoprazole breath test is a reliable, rapid, and noninvasive probe of CYP2C19 and seems to be a useful tool to optimize drug therapy metabolized by CYP2C19

Rapid Identification of the Hepatic Cytochrome P450 2C19 Activity Using a Novel and Noninvasive [13C]Pantoprazole Breath Test

We tested the hypothesis that the stable isotope [13C]pantoprazole is O-demethylated by cytochrome P450 CYP2C19 and that the 13CO2 produced and exhaled in breath as a result can serve as a safe, rapid, and noninvasive phenotyping marker of CYP2C19 activity in vivo. Healthy volunteers who had been genotyped for the CYP2C19*2, CYP2C19*3, and CYP2C19*17 alleles were administered a single oral dose of [13C]pantoprazole sodium-sesquihydrate (100 mg) with 2.1 g of sodium bicarbonate. Exhaled 13CO2 and 12CO2 were measured by IR spectroscopy before (baseline) and 2.5 to 120 min after dosing. Ratios of 13CO2/12CO2 after [13C]pantoprazole relative to 13CO2/12CO2 at baseline were expressed as change over baseline (DOB). Maximal DOB, DOB15 to DOB120, and area under the DOB versus time curve (AUC0–120 and AUC0–∞) were significantly different among three genotype groups (CYP2C19*1/*1, n = 10; CYP2C19*1/*2 or CYP2C19*1/*3, n = 10; and CYP2C19*2/*2, n = 5) with predicted extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs) of CYP2C19, respectively (Kruskal-Wallis test, p < 0.01); linear regression analysis indicated a gene-dose effect relationship (r2 ranged between 0.236 and 0.522; all p < 0.05). These breath test indices were significantly lower in PMs than IMs (p < 0.05) or EMs (p < 0.01) of CYP2C19. [13C]Pantoprazole plasma exposure showed significant inverse correlation with breath test indices in the respective subjects (Pearson r = -0.74; p = 0.038). These feasibility data suggest that the [13C]pantoprazole breath test is a reliable, rapid, and noninvasive probe of CYP2C19 and seems to be a useful tool to optimize drug therapy metabolized by CYP2C19