The Species-Dependent Metabolism of Efavirenz Produces a Nephrotoxic Glutathione Conjugate in Rats

Mutlib, Abdul; Gerson, Ronald J.; Meunier, Paul C.; Haley, Patrick J.; Chen, Hao; Gan, Liang‐Shang; Davies, Meirion; Gemzik, Brian; Christ, David D.; Krahn, David F.; Markwalder, Jay A.; Seitz, Steven P.; Robertson, Richard T.; Miwa, Gerald T.

doi:10.1006/taap.2000.9055

Cited by 102 publications

(62 citation statements)

References 34 publications

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“…In preclinical and clinical studies (8,21,22), efavirenz N-glucuronide has been detected in urine, plasma, and bile samples. Indeed, a recent in vitro study has reported that efavirenz can undergo direct N-glucuronidation and that this reaction is catalyzed by the human UDP-glucuronsyltransferase 2B7 (UGT2B7) (3).…”

mentioning

confidence: 99%

Contribution of N-Glucuronidation to Efavirenz Elimination In Vivo in the Basal and Rifampin-Induced Metabolism of Efavirenz

Cho

Ogburn

Jones

et al. 2011

Antimicrob Agents Chemother

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In this study, the contribution of efavirenz N-glucuronidation to efavirenz elimination in vivo was assessed. In a two-period placebo-controlled crossover trial design, a single 600-mg oral dose of efavirenz was administered to healthy volunteers (n ‫؍‬ 10) pretreated with placebo pills or 600 mg/day rifampin orally for 10 days. Urine and plasma concentrations of efavirenz and 8-hydroxyefavirenz were measured by the liquid chromatography-tandem mass spectrometry method after enzymatic hydrolysis with ␤-glucuronidase (conjugated and unconjugated) and without enzymatic hydrolysis (unconjugated). Pharmacokinetic parameters of efavirenz within the placebo-or rifampin-treated group obtained after enzymatic hydrolysis did not show any statistically significant difference compared with those obtained without enzymatic hydrolysis (P > 0.05; paired t test, two-tailed). The amount of efavirenz excreted over 12 h was significantly larger after enzymatic hydrolysis in both the placebo (P ‫؍‬ 0.007) and rifampin (P ‫؍‬ 0.0001) treatment groups, supporting the occurrence of direct N-glucuronidation of efavirenz, but the relevance of this finding is limited because the amount of efavirenz excreted as unchanged or conjugated in urine is less than 1% of the dose administered. In both the placeboand rifampin-treated groups, plasma concentrations of 8-hydroxyefavirenz and the amount excreted over 12 h were significantly larger (P < 0.00001) after enzymatic hydrolysis than without enzymatic hydrolysis. These findings suggest that although the occurrence of direct efavirenz N-glucuronidation is supported by the urine data, the abundance of efavirenz N-glucuronide in plasma is negligible and that the contribution of the N-glucuronidation pathway to the overall clearance of efavirenz seems minimal.

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mentioning

confidence: 99%

Contribution of N-Glucuronidation to Efavirenz Elimination In Vivo in the Basal and Rifampin-Induced Metabolism of Efavirenz

Cho

Ogburn

Jones

et al. 2011

Antimicrob Agents Chemother

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“…Efavirenz is interesting because it exhibits rat-specific nephrotoxicity that is not observed in either monkey or human (Mutlib et al, 1999). The proximal toxic metabolite is formed only in rats through the formation and subsequent processing of the GSH conjugate to a sulfate metabolite, which was postulated to be responsible for the species-specific renal toxicity in rats (Mutlib et al, 2000). Metabolism studies showed that rodent-specific glutathione S-transferase (GST) formed a glutathione conjugate of a sulfate metabolite (Fig.…”

Section: G-glutamyl Transpeptidasementioning

confidence: 99%

Going Beyond Common Drug Metabolizing Enzymes: Case Studies of Biotransformation Involving Aldehyde Oxidase, -Glutamyl Transpeptidase, Cathepsin B, Flavin-Containing Monooxygenase, and ADP-Ribosyltransferase

Pw¹,

Zhang²,

Js³

et al. 2016

Drug Metabolism and Disposition

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The significant roles that cytochrome P450 (P450) and UDPglucuronosyl transferase (UGT) enzymes play in drug discovery cannot be ignored, and these enzyme systems are commonly examined during drug optimization using liver microsomes or hepatocytes. At the same time, other drug-metabolizing enzymes have a role in the metabolism of drugs and can lead to challenges in drug optimization that could be mitigated if the contributions of these enzymes were better understood. We present examples (mostly from Genentech) of five different non-P450 and non-UGT enzymes that contribute to the metabolic clearance or bioactivation of drugs and drug candidates. Aldehyde oxidase mediates a unique amide hydrolysis of ,7-tetrahydro-1-benzothiophene-2-carboxamide), leading to high clearance of the drug. Likewise, the rodent-specific ribose conjugation by ADP-ribosyltransferase leads to high clearance of an interleukin-2-inducible T-cell kinase inhibitor. Metabolic reactions by flavin-containing monooxygenases (FMO) are easily mistaken for P450-mediated metabolism such as oxidative defluorination of 4-fluoro-N-methylaniline by FMO. Gamma-glutamyl transpeptidase is involved in the initial hydrolysis of glutathione metabolites, leading to formation of proximate toxins and nephrotoxicity, as is observed with cisplatin in the clinic, or renal toxicity, as is observed with efavirenz in rodents. Finally, cathepsin B is a lysosomal enzyme that is highly expressed in human tumors and has been targeted to release potent cytotoxins, as in the case of brentuximab vedotin. These examples of non-P450-and non-UGT-mediated metabolism show that a more complete understanding of drug metabolizing enzymes allows for better insight into the fate of drugs and improved design strategies of molecules in drug discovery.

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“…Preliminary studies in rats have suggested that high doses of EFV induce nephrotoxicity, expressed by necrosis of proximal tubular epithelial cells. Although humans are exposed to higher levels of EFV, this effect has not been corroborated in patients (Gerson, 1999;Mutlib, 2000). Species selectivity with respect to this toxic effect may result from differences in the production and/or processing of reactive metabolites.…”

Section: Other Toxicitiesmentioning

confidence: 99%

Future Perspectives in NNRTI-Based Therapy: Bases for Understanding Their Toxicity

Blas‐García¹,

Apostolova²,

Esplugues³

2011

Recent Translational Research in HIV/AIDS

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The Species-Dependent Metabolism of Efavirenz Produces a Nephrotoxic Glutathione Conjugate in Rats

Cited by 102 publications

References 34 publications

Contribution of N-Glucuronidation to Efavirenz Elimination In Vivo in the Basal and Rifampin-Induced Metabolism of Efavirenz

Contribution of N-Glucuronidation to Efavirenz Elimination In Vivo in the Basal and Rifampin-Induced Metabolism of Efavirenz

Going Beyond Common Drug Metabolizing Enzymes: Case Studies of Biotransformation Involving Aldehyde Oxidase, -Glutamyl Transpeptidase, Cathepsin B, Flavin-Containing Monooxygenase, and ADP-Ribosyltransferase

Future Perspectives in NNRTI-Based Therapy: Bases for Understanding Their Toxicity

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