title: Complex drug interactions of HIV protease inhibitors 1: inactivation, induction, and inhibition of cytochrome P450 3A by ritonavir or nelfinavir.
abstract: Conflicting drug-drug interaction (DDI) studies with the HIV protease inhibitors (PIs) suggest net induction or inhibition of intestinal or hepatic CYP3A. As part of a larger DDI study in healthy volunteers, we determined the effect of extended administration of two PIs, ritonavir (RTV) or nelfinavir (NFV), or the induction-positive control rifampin on intestinal and hepatic CYP3A activity as measured by midazolam (MDZ) disposition after a 14-day treatment with the PI in either staggered (MDZ ∼12 h after PI) or simultaneous (MDZ and PI coadministered) manner. Oral and intravenous MDZ areas under the plasma concentration-time curves were significantly increased by RTV or NFV and were decreased by rifampin. Irrespective of method of administration, RTV decreased net intestinal and hepatic CYP3A activity, whereas NFV decreased hepatic but not intestinal CYP3A activity. The magnitude of these DDIs was more accurately predicted using PI CYP3A inactivation parameters generated in sandwich-cultured human hepatocytes rather than human liver microsomes.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Kirby
authors.forename: Ann C
authors.initials: AC
authors.lastname: Collier
authors.forename: Evan D
authors.initials: ED
authors.lastname: Kharasch
authors.forename: Dale
authors.initials: D
authors.lastname: Whittington
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Thummel
authors.forename: Jashvant D
authors.initials: JD
authors.lastname: Unadkat
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004789:Enzyme Activation; D004790:Enzyme Induction; D005260:Female; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics; D008875:Middle Aged; D019888:Nelfinavir / Q000009:adverse effects / Q000493:pharmacokinetics*; D012293:Rifampin / Q000097:blood / Q000493:pharmacokinetics; D019438:Ritonavir / Q000009:adverse effects / Q000493:pharmacokinetics*; D013379:Substrate Specificity; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D017320:HIV Protease Inhibitors; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D019888:Nelfinavir; D019438:Ritonavir; D008874:Midazolam; D012293:Rifampin