The species-dependent metabolism of efavirenz produces a nephrotoxic glutathione conjugate in rats.
Efavirenz, a potent nonnucleoside reverse transcriptase inhibitor widely prescribed for the treatment of HIV infection, produces renal tubular epithelial cell necrosis in rats but not in cynomolgus monkeys or humans. This species selectivity in nephrotoxicity could result from differences in the production or processing of reactive metabolites, or both. A detailed comparison of the metabolites produced by rats, monkeys, and humans revealed that rats produce a unique glutathione adduct. The mechanism of formation and role of this glutathione adduct in the renal toxicity were investigated using both chemical and biochemical probes. Efavirenz was labeled at the methine position on the cyclopropyl ring with the stable isotope deuterium, effectively reducing the formation of the cyclopropanol metabolite, an obligate precursor to the glutathione adduct. This substitution markedly reduced both the incidence and severity of nephrotoxicity as measured histologically. Further processing of this glutathione adduct was also important in producing the lesion and was demonstrated by inhibiting gamma-glutamyltranspeptidase with acivicin pretreatment (10 mg/kg, IV) prior to dosing with efavirenz. Again, both the incidence and severity of the nephrotoxicity were reduced, such that four of nine rats given acivicin were without detectable lesions. These studies provide compelling evidence that a species-specific formation of glutathione conjugate(s) from efavirenz is involved in producing nephrotoxicity in rats. Mechanisms are proposed for the formation of reactive metabolites that could be responsible for the renal toxicity observed in rats.
Mutlib
A E
AE
Drug Metabolism and Pharmacokinetics Section, DuPont Pharmaceuticals Company, Stine-Haskell Research Center, Elkton Road, Newark, Delaware 19714, USA.
Gerson
R J
RJ
Meunier
P C
PC
Haley
P J
PJ
Chen
H
H
Gan
L S
LS
Davies
M H
MH
Gemzik
B
B
Christ
D D
DD
Krahn
D F
DF
Markwalder
J A
JA
Seitz
S P
SP
Robertson
R T
RT
Miwa
G T
GT
D000480:Alkynes; D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism*; D048588:Benzoxazines; D003521:Cyclopropanes; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000187:drug effects* / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism*; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009336:Necrosis; D010078:Oxazines / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism* / Q000633:toxicity; D013045:Species Specificity
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D010078:Oxazines; D018894:Reverse Transcriptase Inhibitors; D005978:Glutathione; C098320:efavirenz; C006303:acivicin