Bioavailability assessment and pharmacologic response: impact of first-pass loss when both drug and metabolites are active.

Many drugs with low oral bioavailability due to substantial first-pass hepatic loss form pharmacologically active metabolites. In such cases, the pharmacologic activity after oral administration is greater than anticipated from bioavailability data, based on chemical assay of drug alone. This paper explores the use and meaning of pharmacologic data to assess bioavailability under these circumstances. Two steady-state concepts are introduced: a metabolite-to-drug intravenous delivery rate potency ratio and an effective bioavailability, defined as the ratio of intravenous-to-oral delivery rates of drug required to produce the same response. Using a combined pharmacokinetic-pharmacodynamic model, the impact of various factors on the effective bioavailability and on its estimation, using the intravenous-to-oral dose ratio required to produce the same area under the response time curve after acute administration, are explored. It is proposed that attention be centered more on comparison of rates of administration, or doses, that produce equal responses than on bioavailability per se.