title: Unexpected drug-drug interactions in human immunodeficiency virus (HIV) therapy: induction of UGT1A1 and bile efflux transporters by Efavirenz.
abstract: BACKGROUND
  Efavirenz is an inducer of drug metabolism enzymes. We studied the effect of efavirenz and ritonavir-boosted darunavir on serum unconjugated and conjugated bilirubin, as probes for UGT1A1 and bile transporters.
  
  
  METHODS
  Healthy volunteers were enrolled in a clinical trial. There were 3 periods: Period 1, 10 days of darunavir 900 mg with ritonavir 100 mg once daily; Period 2, 14 days of efavirenz 600 mg with darunavir/ritonavir once daily; and Period 3, 14 days of efavirenz 600 mg once daily. Serum bilirubin (conjugated and unconjugated) concentrations were obtained at baseline, at the end of each phase and at exit.
  
  
  RESULTS
  We recruited 7 males and 5 females. One subject developed grade 3 hepatitis on efavirenz and was excluded. Mean serum unconjugated bilirubin concentrations were 6.09 μmol/L (95% confidence interval [CI], 4.99 to 7.19) at baseline, 5.82 (95% CI, 4.88 to 6.76) after darunavir/ritonavir, 4.00 (95% CI, 2.92 to 5.08) after darunavir/ritonavir with efavirenz, 3.55 (95% CI, 2.58 to 4.51) after efavirenz alone and 5.27 (95% CI, 3.10 to 7.44) at exit (P <0.01 for the efavirenz phases). Mean serum conjugated bilirubin concentrations were 3.55 μmol/L (95% CI, 2.73 to 4.36) at baseline, 3.73 (95% CI, 2.77 to 4.68) after darunavir/ritonavir, 2.91 (95% CI, 2.04 to 3.78) after darunavir/ritonavir with efavirenz, 2.64 (95% CI, 1.95 to 3.33) after efavirenz alone and 3.55 (95% CI, 2.19 to 4.90) at exit (P <0.05 for the efavirenz phases).
  
  
  CONCLUSIONS
  Efavirenz decreased unconjugated bilirubin by 42%, suggesting UGT1A1 induction. Efavirenz also decreased conjugated bilirubin by 26%, suggesting induction of bile efflux transporters. Ritonavir-boosted darunavir had no effect on bilirubin concentrations. These results indicate that efavirenz may reduce concentrations of drugs or endogenous substances metabolized by UGT1A1 or excreted by bile efflux transporters.
authors.affiliation: Yong Loo Lin School of Medicine, National University of Singapore, Singapore. mdcllsu@nus.edu.sg
authors.forename: Lawrence S U
authors.initials: LS
authors.lastname: Lee
authors.forename: Paul
authors.initials: P
authors.lastname: Pham
authors.forename: Charles
authors.initials: C
authors.lastname: Flexner
mesh_terms: D000328:Adult; D000368:Aged; D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use; D048588:Benzoxazines / Q000494:pharmacology*; D001692:Biological Transport; D016001:Confidence Intervals; D003521:Cyclopropanes; D000069454:Darunavir; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D014453:Glucuronosyltransferase / Q000096:biosynthesis* / Q000097:blood; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors; D006801:Humans; D033162:Incidental Findings; D008297:Male; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D019438:Ritonavir / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D055815:Young Adult; D000099148:UGT1A1 Enzyme
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D000069454:Darunavir; D014453:Glucuronosyltransferase; D017320:HIV Protease Inhibitors; D026901:Membrane Transport Proteins; D019438:Ritonavir; D013449:Sulfonamides; D000099148:UGT1A1 Enzyme; C098320:efavirenz