PT  - JOURNAL ARTICLE
AU  - A. E. Mutlib
AU  - H. Chen
AU  - G. A. Nemeth
AU  - J. A. Markwalder
AU  - S. P. Seitz
AU  - L. S. Gan
AU  - D. D. Christ
TI  - Identification and Characterization of Efavirenz Metabolites by Liquid Chromatography/Mass Spectrometry and High Field NMR: Species Differences in the Metabolism of Efavirenz
DP  - 1999 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 1319--1333
VI  - 27
IP  - 11
4099  - http://dmd.aspetjournals.org/content/27/11/1319.short
4100  - http://dmd.aspetjournals.org/content/27/11/1319.full
SO  - Drug Metab Dispos1999 Nov 01; 27
AB  - Efavirenz (Sustiva, Fig. 1) is a potent and specific inhibitor of HIV-1 reverse transcriptase approved for the treatment of HIV infection. To examine the potential differences in the metabolism among species, liquid chromatography/mass spectrometry profiles of efavirenz metabolites in urine of rats, guinea pigs, hamsters, cynomolgus monkeys, and humans were obtained and compared. The metabolites of efavirenz were isolated, and structures were determined unequivocally by mass spectral and NMR analyses. Efavirenz was metabolized extensively by all the species as evidenced by the excretion of none or trace quantities of parent compound in urine. Significant species differences in the metabolism of efavirenz were observed. The major metabolite excreted in the urine of all species was the O-glucuronide conjugate (M1) of the 8-hydroxylated metabolite. Efavirenz was also metabolized by direct conjugation with glucuronic acid, forming theN-glucuronide (M2) in all five species. The sulfate conjugate of 8-OH efavirenz (M3) was found in the urine of rats and cynomolgus monkeys but not in humans. In addition to the aromatic ring-hydroxylated products, metabolites with a hydroxylated cyclopropane ring (at C14) were also isolated. GSH-related products of efavirenz were identified in rats and guinea pigs. The cysteinylglycine adduct (M10), formed from the GSH adduct (M9), was found in significant quantities in only rat and guinea pig urine and was not detected in other species. In vitro metabolism studies were conducted to show that the GSH adduct was produced from the cyclopropanol intermediate (M11) in the presence of only rat liver and kidney subcellular fractions and was not formed by similar preparations from humans or cynomolgus monkeys. These studies indicated the existence of a specific glutathione-S-transferase in rats capable of metabolizing the cyclopropanol metabolite (M11) to the GSH adduct, M9. The biotransformation pathways of efavirenz in different species were proposed based on some of the in vitro results. The American Society for Pharmacology and Experimental Therapeutics