The authors studied the effect of rifampin, a dual inducer of CYP3A and P-glycoprotein, on the pharmacokinetics and pharmacodynamics of risperidone in humans. Ten healthy male subjects were treated daily for 7 days with 600 mg rifampin or with placebo. On day 6, a single dose of 1 mg risperidone was administered. Plasma risperidone and 9-hydroxyrisperidone concentrations were measured. Rifampin significantly decreased the mean area under the plasma concentration-time curve by 51% for risperidone, by 43% for 9-hydroxyrisperidone, and by 45% for the active moieties (risperidone + 9-hydroxyrisperidone). Rifampin also decreased the peak plasma concentration of risperidone by 38%, 9-hydroxyrisperidone by 46%, and the active moieties by 41%. The apparent oral clearance of risperidone approximately doubled after rifampin treatment. Thus, rifampin reduced the exposure to risperidone, probably because of a decrease in its bioavailability through the induction of CYP3A and probably P-glycoprotein.

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.

We developed a rapid and sensitive method for determining efavirenz, 8-hydroxyefavirenz, and 8,14-dihydroxyefavirenz in human plasma simultaneously using liquid chromatography-tandem mass spectrometry (LC-MS-MS). Three compounds and ritonavir, an internal standard, were extracted from plasma using ethyl acetate in the presence of 0.1 M sodium carbonate after incubation of b-glucuronidase (500 U). After drying the organic layer, the residue was reconstituted in mobile phase (acetonitrile:20 mM ammonium acetate, 90:10, v/v) and injected onto a reversed-phase C 18 column. The isocratic mobile phase was eluted at 0.2 mL min -1 . The ion transitions monitored in multiple reaction-monitoring mode were m/z 314 ? 244, 330 ? 258, 346 ? 262, and 721 ? 296 for efavirenz, 8-hydroxyefavirenz, 8,14-dihydroxyefavirenz, and ritonavir, respectively. The retention time is 1.93, 1.70, 1.52, and 1.82 min for efavirenz, 8-hydroxyefavirenz, 8,14-dihydroxyefavirenz, and ritonavir, respectively. The coefficients of variation of the assay precision were less than 10.7%, and the accuracy was 90-111%. The lower limits of quantification (LLOQ) were 5 ng mL -1 for efavirenz and 8-hydroxyefavirenz. This method was used to measure the plasma concentrations of efavirenz and its metabolites from healthy volunteers after a single 600 mg oral dose of efavirenz. This analytical method is a very rapid, sensitive, and accurate to determine the pharmacokinetic profiles of efavirenz including its metabolites.

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