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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION
Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana
We used human liver microsomes (HLMs) and recombinant cytochromes P450
(P450s) to identify the routes of efavirenz metabolism and the P450s involved.
In HLMs, efavirenz undergoes primary oxidative hydroxylation to
8-hydroxyefavirenz (major) and 7-hydroxyefavirenz (minor) and secondary
metabolism to 8,14-dihydroxyefavirenz. The formation of 8-hydroxyefavirenz in
two HLMs showed sigmoidal kinetics (average apparent Km,
20.2 µM; Vmax, 140 pmol/min/mg protein; and Hill
coefficient, 1.5), whereas that of 7-hydroxyefavirenz formation was
characterized by hyperbolic kinetics (Km, 40.1 µM and
Vmax, 20.5 pmol/min/mg protein). In a panel of 10 P450s,
CYP2B6 formed 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz from efavirenz
(10 µM) at the highest rate. The Km value for the
formation of 8-hydroxyefavirenz in CYP2B6 derived from hyperbolic Eq. 12.4
µM) was close to that obtained in HLMs (Km, 20.2
µM). None of the P450s tested showed activity toward 7-hydroxylation of
efavirenz. When 8-hydroxyefavirenz (2.5 µM) was used as a substrate,
8,14-dihydroxyefavirenz was formed by CYP2B6 at the highest rate, and its
kinetics showed substrate inhibition (Ksi, 
94 µM
in HLMs and 234 µM in CYP2B6). In a panel of 11 HLMs,
8-hydroxyefavirenz and 8,14-dihydroxyefavirenz formation rates from efavirenz
(10 µM) correlated significantly with the activity of CYP2B6 and CYP3A.
N,N',N"-Triethylenethiophosphoramide (thioTEPA; 50
µM) inhibited the formation rates of 8-hydroxyefavirenz and
8,14-dihydroxyefavirenz from efavirenz (10 µM) by ≥60% in HLMs) and
CYP2B6, with Ki values < 4 µM. In conclusion, CYP2B6
is the principal catalyst of efavirenz sequential hydroxylation. Efavirenz
systemic exposure is likely to be subject to interindividual variability in
CYP2B6 activity and to drug interactions involving this isoform. Efavirenz may
be a valuable phenotyping tool to study the role of CYP2B6 in human drug
metabolism.
Address correspondence to: Dr. Zeruesenay Desta, Assistant Professor of Medicine and Pharmacology and Toxicology, Indiana University School of Medicine, Department of Medicine, Division of Clinical Pharmacology, 1001 West 10th Street, WD Myers Bldg., W7123, Indianapolis, IN 46202. E-mail: zdesta{at}iupui.edu
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