radafaxine and efavirenz

To characterize the effect of efavirenz on bupropion hydroxylation as a marker of cytochrome P450 (CYP) 2B6 activity in healthy subjects.. Thirteen subjects received a single oral dose of bupropion SR 150 mg before and after 2 weeks of efavirenz administration for comparison of bupropion and hydroxybupropion pharmacokinetics. Efavirenz plasma concentrations were also assessed. Subjects were genotyped for CYP2B6 (G516T, C1459T, and A785G), CYP3A4 (A-392G), CYP3A5 (A6986G), and multidrug resistance protein 1 (C3435T).. The area under the concentration vs. time curve ratio of hydroxybupropion:bupropion increased 2.3-fold after efavirenz administration (P=0.0001). Bupropion area under the concentration vs. time curve and Cmax decreased by 55% and 34%, respectively (P<0.002). None of the CYP2B6 or CYP3A genotypes evaluated were associated with a difference in bupropion or efavirenz clearance. The 2 individuals homozygous for multidrug resistance protein 1 3435-T/T had 2.5- and 1.8-fold greater bupropion and efavirenz clearance, respectively, relative to C/C and C/T individuals (P<0.05).. Our results confirm that efavirenz induces CYP2B6 enzyme activity in vivo, as demonstrated by an increase in bupropion hydroxylation after 2 weeks of efavirenz administration.

Topics: Adult; Alkynes; Anti-HIV Agents; Antidepressive Agents, Second-Generation; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Bupropion; Cyclopropanes; Cytochrome P-450 CYP2B6; Delayed-Action Preparations; Drug Interactions; Enzyme Induction; Female; Genetic Variation; Humans; Hydroxylation; Male; Middle Aged; Oxidoreductases, N-Demethylating; Pharmacogenetics; Young Adult

Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of drugs such as bupropion, efavirenz, propofol, and selegiline, among others. More than 200 commonly prescribed drugs and other xenobiotics were examined for their ability to inhibit CYP2B6-mediated bupropion hydroxylase activity. Thirty compounds were found exhibiting greater than 50% inhibition at 30 microM. Inhibitors of CYP2B6 were identified from a wide variety of therapeutic classes. The 2 platelet aggregation inhibitors, clopidogrel and ticlopidine, were both identified as potent inhibitors (IC50 = 0.0206 and 0.149 microM, respectively). Other inhibitors (IC50 < 1 microM) included clotrimazole, itraconazole, sertraline, and raloxifene. These in vitro data were used along with clinical pharmacokinetic information in the prediction of potential drug-drug interactions that could occur by inhibition of CYP2B6. Although few drugs tested are expected to cause drug interactions, clopidogrel and ticlopidine were identified as being of concern as potential inhibitors of clinical relevance. These findings are discussed in context to potential drug interactions that could be observed between these agents and drugs for which CYP2B6 is involved in metabolism.

Topics: Algorithms; Alkynes; Antidepressive Agents, Second-Generation; Antifungal Agents; Area Under Curve; Benzoxazines; Bupropion; Clopidogrel; Clotrimazole; Cyclopropanes; Cytochrome P-450 CYP2B6; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Humans; Itraconazole; Kinetics; Microsomes, Liver; Molecular Structure; Oxazines; Platelet Aggregation Inhibitors; Raloxifene Hydrochloride; Reverse Transcriptase Inhibitors; Selective Estrogen Receptor Modulators; Selective Serotonin Reuptake Inhibitors; Sertraline; Ticlopidine; Xenobiotics