TY - JOUR T1 - Influence of UGT1A1 and SLCO1B1 Polymorphisms and Efavirenz on Bilirubin Disposition in Healthy Volunteers JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.119.089052 SP - dmd.119.089052 AU - Kimberly S. Collins AU - Ingrid F. Metzger AU - Brandon T. Gufford AU - Jessica Lu AU - Elizabeth B. Medeiros AU - Victoria M. Pratt AU - Todd C. Skaar AU - Zeruesenay Desta Y1 - 2019/01/01 UR - http://dmd.aspetjournals.org/content/early/2019/12/30/dmd.119.089052.abstract N2 - Chronic administration of efavirenz is associated with decreased serum bilirubin levels, probably through induction of UGT1A1. We assessed the impact of efavirenz monotherapy and UGT1A1 phenotypes on total, conjugated, and unconjugated serum bilirubin levels in healthy volunteers. Healthy volunteers were enrolled into a clinical study designed to address efavirenz pharmacokinetics, drug interactions, and pharmacogenetics. Volunteers received multiple oral doses (600 mg/d for 17 days) of efavirenz. Serum bilirubin levels were obtained at study entry and 1 week after completion of the study. DNA genotyping was performed for UGT1A1 (*80 (C>T), *6 (G>A), *28 (TA7), *36 (TA5) and *37 (TA8)) and for SLCO1B1 (*5 (521T>C) and *1b (388A>G) variants. Diplotype predicted phenotypes were classified as normal, intermediate and slow metabolizers. Compared to bilirubin levels at screening, treatment with efavirenz significantly reduced total, conjugated, and unconjugated bilirubin. After stratification by UGT1A1 phenotypes, there was a significant decrease in total bilirubin among all phenotypes, conjugated bilirubin among intermediate metabolizer, and unconjugated bilirubin among normal and intermediate metabolizers. The data also show that UGT1A1 genotype predicts serum bilirubin levels at baseline, but this relationship is lost after efavirenz treatment. SLCO1B1 genotypes did not predict bilirubin levels at baseline or after efavirenz treatment. Our data suggest that efavirenz may alter bilirubin disposition mainly through induction of UGT1A1 metabolism and efflux through MRP2.SIGNIFICANCE STATEMENT Efavirenz likely alters the pharmacokinetics of coadministered drugs, potentially causing lack of efficacy or increased adverse effects, as well as the disposition of endogenous compounds relevant in homeostasis through upregulation of UGT1A1 and MRP2. Measurement of unconjugated and conjugated bilirubin during new drug development may provide mechanistic understanding regarding enzyme and transporters modulated by the new drug. . ER -