Hepatic but not intestinal CYP3A4 displays dose-dependent induction by efavirenz in humans.
OBJECTIVE
The capacity of the non-nucleoside reverse transcriptase inhibitor efavirenz to induce either liver CYP3A4 or intestinal CYP3A4, or both, as well as intestinal P-glycoprotein, was evaluated in healthy volunteers during and after a 10-day treatment course with two different daily doses.


METHODS
Cohorts of 12 healthy subjects were randomized (2:1) to receive either efavirenz or placebo orally for 10 days. The first cohort received 200 mg efavirenz and the second cohort received 400 mg efavirenz daily. Liver CYP3A4 activity was evaluated on 9 different occasions with use of the erythromycin breath test (ERMBT). Intestinal biopsy specimens were obtained before the first dose of efavirenz and on the day after administration of the last dose to measure intestinal CYP3A4 and P-glycoprotein contents by immunoblotting. Efavirenz plasma levels were measured by HPLC, and pharmacokinetic parameters were determined by standard noncompartmental methods.


RESULTS
Efavirenz significantly increased the mean ERMBT result in a dose- and time-dependent manner, with a 55% mean induction at 400 mg and a 33% mean induction at 200 mg (P <.01, compared with placebo for each treatment). The efavirenz AUC on day 10 correlated with the magnitude of induction (day 11/day 1 ERMBT ratio) when the two dose groups were combined (r = 0.509; P =.04). In contrast, efavirenz treatment had no detectable effect on intestinal CYP3A4 or P-glycoprotein.


CONCLUSIONS
Efavirenz is an inducer of liver CYP3A4 in healthy volunteers, and interpatient differences in magnitude of induction is partly explained by variation in systemic drug exposure. However, efavirenz did not appear to induce intestinal CYP3A4 or intestinal P-glycoprotein. These results suggest that drug interactions caused by induction of CYP3A4 can be liver specific.
Mouly
Stéphane
S
General Clinical Research Center, University of North Carolina, Chapel Hill 27599, USA. pbwatkins@med.unc.edu
Lown
Kenneth S
KS
Kornhauser
David
D
Joseph
Jeffrey L
JL
Fiske
William D
WD
Benedek
Irma H
IH
Watkins
Paul B
PB
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis; D000293:Adolescent; D000328:Adult; D000480:Alkynes; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D048588:Benzoxazines; D001944:Breath Tests; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004790:Enzyme Induction / Q000187:drug effects; D004917:Erythromycin; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007422:Intestines / Q000187:drug effects / Q000201:enzymology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D010078:Oxazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis; D011500:Protein Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*
D018435:ATP Binding Cassette Transporter, Subfamily B; D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; D011500:Protein Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C104464:CYP3A protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz