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Complex drug interactions of HIV protease inhibitors 1: inactivation, induction, and inhibition of cytochrome P450 3A by ritonavir or nelfinavir.

Publication ,  Journal Article
Kirby, BJ; Collier, AC; Kharasch, ED; Whittington, D; Thummel, KE; Unadkat, JD
Published in: Drug Metab Dispos
June 2011

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.

Duke Scholars

Published In

Drug Metab Dispos

DOI

EISSN

1521-009X

Publication Date

June 2011

Volume

39

Issue

6

Start / End Page

1070 / 1078

Location

United States

Related Subject Headings

  • Young Adult
  • Tissue Distribution
  • Substrate Specificity
  • Ritonavir
  • Rifampin
  • Pharmacology & Pharmacy
  • Nelfinavir
  • Middle Aged
  • Midazolam
  • Male
 

Citation

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Kirby, B. J., Collier, A. C., Kharasch, E. D., Whittington, D., Thummel, K. E., & Unadkat, J. D. (2011). Complex drug interactions of HIV protease inhibitors 1: inactivation, induction, and inhibition of cytochrome P450 3A by ritonavir or nelfinavir. Drug Metab Dispos, 39(6), 1070–1078. https://doi.org/10.1124/dmd.110.037523
Kirby, Brian J., Ann C. Collier, Evan D. Kharasch, Dale Whittington, Kenneth E. Thummel, and Jashvant D. Unadkat. “Complex drug interactions of HIV protease inhibitors 1: inactivation, induction, and inhibition of cytochrome P450 3A by ritonavir or nelfinavir.Drug Metab Dispos 39, no. 6 (June 2011): 1070–78. https://doi.org/10.1124/dmd.110.037523.
Kirby BJ, Collier AC, Kharasch ED, Whittington D, Thummel KE, Unadkat JD. Complex drug interactions of HIV protease inhibitors 1: inactivation, induction, and inhibition of cytochrome P450 3A by ritonavir or nelfinavir. Drug Metab Dispos. 2011 Jun;39(6):1070–8.
Kirby, Brian J., et al. “Complex drug interactions of HIV protease inhibitors 1: inactivation, induction, and inhibition of cytochrome P450 3A by ritonavir or nelfinavir.Drug Metab Dispos, vol. 39, no. 6, June 2011, pp. 1070–78. Pubmed, doi:10.1124/dmd.110.037523.
Kirby BJ, Collier AC, Kharasch ED, Whittington D, Thummel KE, Unadkat JD. Complex drug interactions of HIV protease inhibitors 1: inactivation, induction, and inhibition of cytochrome P450 3A by ritonavir or nelfinavir. Drug Metab Dispos. 2011 Jun;39(6):1070–1078.
Journal cover image

Published In

Drug Metab Dispos

DOI

EISSN

1521-009X

Publication Date

June 2011

Volume

39

Issue

6

Start / End Page

1070 / 1078

Location

United States

Related Subject Headings

  • Young Adult
  • Tissue Distribution
  • Substrate Specificity
  • Ritonavir
  • Rifampin
  • Pharmacology & Pharmacy
  • Nelfinavir
  • Middle Aged
  • Midazolam
  • Male