title: Alteration in cytochrome P450 3A4 activity as measured by a urine cortisol assay in HIV-1-infected pregnant women and relationship to antiretroviral pharmacokinetics.
abstract: OBJECTIVE
  Pregnancy results in physiological changes altering the pharmacokinetics of drugs metabolized by cytochrome P450 3A4 (CYP3A4). The urinary ratio of 6-β hydroxycortisol to cortisol (6βHF : F) is a marker of CYP3A4 induction. We sought to evaluate its change in antiretroviral (ARV)-treated HIV-1-infected women and to relate this change to ARV pharmacokinetics.
  
  
  METHODS
  Women receiving various ARVs had pharmacokinetic evaluations during the third trimester of pregnancy (>30 weeks) and postpartum with determination of 6βHF : F carried out on the same days. The Wilcoxon signed rank test was used to compare the ratio antepartum to postpartum. The relationship between the change in ratio and the change in pharmacokinetics was analysed using Kendall's tau.
  
  
  RESULTS
  6βHF : F ratios were available for 107 women antepartum, with 54 having postpartum values. The ratio was higher antepartum (P=0.033) (median comparison 1.35; 95% confidence interval 1.01, 1.81). For 71 women taking a protease inhibitor (PI), the antepartum vs. postpartum 6βHF : F comparison was marginally significant (P=0.058). When the change in the 6βHF : F ratio was related to the change in the dose-adjusted ARV area under the plasma concentration vs. time curve (AUC) between antepartum and postpartum, the 35 subjects in the lopinavir/ritonavir (LPV/r) arms demonstrated an inverse relationship (P=0.125), albeit this correlation did not reach statistical significance.
  
  
  CONCLUSIONS
  A 35% increase in the urinary 6βHF : F ratio was measured during late pregnancy compared with postpartum, indicating that CYP3A induction occurs during pregnancy. The trend towards an inverse relationship between the change in the 6βHF : F ratio and the change in the LPV AUC antepartum vs. postpartum suggests that CYP3A induction may be one mechanism behind altered LPV exposure during pregnancy.
authors.affiliation: University of California, San Francisco, CA, USA.
authors.forename: F T
authors.initials: FT
authors.lastname: Aweeka
authors.forename: C
authors.initials: C
authors.lastname: Hu
authors.forename: L
authors.initials: L
authors.lastname: Huang
authors.forename: B M
authors.initials: BM
authors.lastname: Best
authors.forename: A
authors.initials: A
authors.lastname: Stek
authors.forename: P
authors.initials: P
authors.lastname: Lizak
authors.forename: S K
authors.initials: SK
authors.lastname: Burchett
authors.forename: J S
authors.initials: JS
authors.lastname: Read
authors.forename: H
authors.initials: H
authors.lastname: Watts
authors.forename: M
authors.initials: M
authors.lastname: Mirochnick
authors.forename: E V
authors.initials: EV
authors.lastname: Capparelli
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism / Q000652:urine / Q000821:virology; D015497:HIV-1; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000652:urine; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism / Q000652:urine; D011263:Pregnancy Trimester, Third / Q000378:metabolism; D011446:Prospective Studies
chemical_list: D019380:Anti-HIV Agents; C001380:6 beta-hydroxycortisol; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D006854:Hydrocortisone
keywords: antiretrovirals; cortisol; cytochrome p450; pharmacokinetics; pregnancy