Physiological modeling to understand the impact of enzymes and transporters on drug and metabolite data and bioavailability estimates.

PURPOSE: To obtain mathematical solutions that correlate drug and metabolite exposure and systemic bioavailability (F (sys)) with physiological determinants, transporters and enzymes.
METHODS: A series of physiologically-based pharmacokinetic (PBPK) models that included renal excretion and sequential metabolism within the intestine and/or liver as metabolite formation organs were developed. The area under the curve for drug (AUC) and formed metabolite (AUC{mi,P}) were solved by matrix inversion.
RESULTS: The PBPK models revealed that AUC{mi,P} was dependent on dispositional parameters (transport and elimination) for the drug and metabolite. The solution was unique for each metabolite formation organ and was dependent on the type of drug and metabolite elimination organs. The AUC ratio of the formed metabolite after oral and intravenous drug dosing was useful for determination of the fraction absorbed (F (abs)) and not the systemic bioavailability (F (sys)) when either intestine or liver was the only drug elimination organ.
CONCLUSIONS: The AUC ratio of the formed metabolite after oral and intravenous drug dosing differed from that for drug and would not provide F (sys). However, the AUC ratio of the formed metabolite for oral and intravenous drug dosing furnished the estimate of F (abs) when intestine or liver was the only drug metabolic organ.