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Efavirenz Induces CYP450 2B6 Activity as Measured by Bupropion Hydroxylation in Healthy Subjects
Sarah Robertson*1, F Maldarelli2, V Natarajan3, E Formentini4, R Alfaro5, and S Penzak5
1US Food and Drug Admin, Silver Spring, MD, US; 2NCI, Bethesda, MD, US; 3SAIC-Frederick, MD, US; 4NIH, Bethesda, MD, US; and 5Clinical Res Ctr, NIH, Bethesda, MD, US
Background: Cytochrome P450 (CYP) 2B6 is a
polymorphic hepatic enzyme that metabolizes multiple therapeutic agents, including
efavirenz (EFV), methadone, cyclophosphamide, and bupropion. Results from in
vitro studies are conflicting as to whether EFV induces or inhibits CYP2B6
metabolism. The effect of EFV on CYP2B6 has not been evaluated in humans. The
purpose of this study was to characterize the influence of EFV on bupropion
hydroxylation, a validated marker of CYP2B6 activity, in healthy human subjects.
Methods: In phase I, subjects received a single oral
dose of bupropion SR 150 mg in the fasted state, followed by serial blood
collection over 48 hours for determination of bupropion and hydroxybupropion
(OH-bupropion) plasma concentrations. Following 2 weeks of EFV administration (600
mg at bedtime), subjects received a second dose of bupropion with repeat blood sampling
over 48 hours (phase II). Bupropion and OH-bupropion pharmacokinetic parameters
were compared between phases I and II to assess for a difference in bupropion
hydroxylation. In addition, allelic variants of CYP2B6 (G516T, C1459, and
A785G) were determined to evaluate their potential impact on bupropion
hydroxylation in the presence and absence of EFV.
Results: The study was completed by 13 healthy males
and females. The ratio of OH-bupropion:bupropion AUC increased 2.3-fold from phase
I to phase II (p = 0.0001). Bupropion AUC and Cmax decreased
by 55% and 34%, respectively (p <0.002), while OH-bupropion AUC was
unchanged. OH-bupropion T1/2 decreased from 24 hours to 16 hours (p
= 0.0002). None of the CYP2B6 genotypes evaluated appeared to affect bupropion
PK in the presence or absence of EFV.
Conclusions: Our results indicate that EFV induces
CYP2B6 metabolism in vivo, as demonstrated by induction of bupropion
hydroxylation. Interestingly, OH-bupropion AUC was unchanged, while its T1/2
was significantly decreased. This suggests EFV may also increase the
elimination of OH-bupropion, a pharmacologically active metabolite whose
elimination has not been described. A 55% decrease in bupropion exposure may
have important clinical consequences for patients on EFV therapy who take bupropion
for smoking cessation or the treatment of depression. Other drugs metabolized
by CYP2B6 may also have reduced exposure when coadministered with EFV; as such,
CYP2B6 substrates should be used with caution in patients receiving EFV.
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