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BACKGROUND: Efavirenz exhibits multiple interactions with drug-metabolizing enzymes and transporters, and for this reason efavirenz-based HIV therapy is associated with altered pharmacokinetics of coadministered drugs. Probably by the same mechanism, efavirenz-based HIV therapy affects the disposition of endogenous compounds, but this effect is difficult to directly link with efavirenz because it is used in combination with other drugs. OBJECTIVES: To explore the effect of efavirenz monotherapy on biochemical laboratory values in a clinical trial of healthy volunteers. METHODS: Men and women (aged 18-49 years) with body mass index ≤32 who were assessed to be healthy based on medical history, physical examination, and standard laboratory screening received a single (600 mg) and multiple doses (600 mg/d for 17 days) of efavirenz orally. This trial was designed to determine the pharmacokinetics and drug interactions of efavirenz. As part of this study, analysis of serum chemistries that were measured at study entry (screening) and 1 week after completion of the multiple dose study (exit) is reported. RESULTS: Data from 60 subjects who fully completed and 13 subjects who partially completed the study are presented. Total bilirubin was substantially reduced at exit (by ~30%, with large intersubject variability) compared with screening values (P < 0.0001). The percent changes were in part explained by the intersubject differences in baseline total bilirubin because there was a significant correlation between baseline (screening) values and percent change at exit (r = 0.50; P < 0.0001). Hemoglobin and absolute neutropenia were also substantially decreased at exit compared with screening, but this may be due to intensive blood sampling rather than direct effect of efavirenz on these parameters. No significant correlation was found between percent change in hemoglobin versus percent change in bilirubin, indicating the effect of efavirenz on bilirubin is independent of its effects on hemoglobin. CONCLUSIONS: Efavirenz monotherapy significantly lowers plasma total bilirubin concentration in healthy volunteers independent of its effect on hemoglobin, probably through its effects on bilirubin metabolism and transport (uptake and efflux). These findings help explain reversal by efavirenz of hyperbilirubinemia induction observed by some protease inhibitor antiretroviral drugs (eg, atazanavir). Besides its well-documented role on drug interactions, efavirenz may alter the disposition of endogenous compounds relevant in physiologic homeostasis through its interaction with drug metabolizing enzymes and/or drug transporters. ClinicalTrials.gov identifier: NCT00668395.
RESUMO
OBJECTIVES: Androgens, especially dihydrotestosterone, have been postulated to modify the risk of prostate cancer. 3-Beta-hydroxysteroid dehydrogenase1 (HSD3B1) and uridine diphosphate-glucuronosyltransferase 2B17 (UGT2B17) are enzymes that inactivate dihydrotestosterone in the prostate and may affect dihydrotestosterone concentration in prostatic tissue. The purpose of this study was to determine whether polymorphisms in HSD3B1 and UGT2B17 increase the risk of prostate cancer. METHODS: In a case-control study of 356 patients with incident primary prostate cancer and 363 age-matched controls, the frequencies of HSD3B1 N367T and UGT2B17 null polymorphisms in genomic DNA were compared between the patients and controls. RESULTS: No evidence was found for a main effect of the HSD3B1 codon 367 polymorphism on prostate cancer risk. However, among white men with family history of prostate cancer, the HSD3B1 367Thr allele was positively associated with prostate cancer (odds ratio 3.0, 95% confidence interval 1.0 to 9.2). A significant association was observed between the UGT2B17 null polymorphism and prostate cancer risk (odds ratio 1.7, 95% confidence interval 1.03 to 2.9). An association with the UGT2B17 null polymorphism was further elevated (odds ratio 2.7, 95% confidence interval 1.1 to 6.5) among individuals with HSD3B1 Asn/Asn genotype. CONCLUSIONS: These results suggest that the HSD3B1 N367T and UGT2B17 null polymorphisms may modify the risk of prostate cancer, particularly among men with a family history of the disease.