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 14 day treatment with the PI in either staggered (MDZ ~12 hrs after PI) or simultaneous (MDZ and PI co-administered) manner. Oral and intravenous MDZ plasma AUCs 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 (SCHHs) rather than human liver microsomes (HLMs).
- CYP induction
- CYP inhibition
- drug-drug interactions
- hepatocytes
- in vitro-in vivo prediction
- liver microsomes
- mechanism-based inhibition
- Received December 6, 2010.
- Accepted March 9, 2011.
- The American Society for Pharmacology and Experimental Therapeutics