Efavirenz induces CYP2B6-mediated hydroxylation of bupropion in healthy subjects.
OBJECTIVE
To characterize the effect of efavirenz on bupropion hydroxylation as a marker of cytochrome P450 (CYP) 2B6 activity in healthy subjects.


METHODS
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).


RESULTS
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).


CONCLUSIONS
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.
Robertson
Sarah M
SM
Office of Clinical Pharmacology, US Food and Drug Administration, Silver Spring, MD 20993, USA. sarah.robertson@fda.hhs.gov
Maldarelli
Frank
F
Natarajan
Ven
V
Formentini
Elizabeth
E
Alfaro
Raul M
RM
Penzak
Scott R
SR
D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood / Q000494:pharmacology*; D018687:Antidepressive Agents, Second-Generation / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D048588:Benzoxazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D016642:Bupropion / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D003692:Delayed-Action Preparations; D004347:Drug Interactions; D004790:Enzyme Induction; D005260:Female; D014644:Genetic Variation; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010597:Pharmacogenetics; D055815:Young Adult
D000480:Alkynes; D019380:Anti-HIV Agents; D018687:Antidepressive Agents, Second-Generation; D048588:Benzoxazines; D003521:Cyclopropanes; D003692:Delayed-Action Preparations; D016642:Bupropion; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz; C496215:radafaxine