​​​​​​​It is generally believed that bioavailability (F) calculated based on systemic concentration area under the curve (AUC) measurements cannot exceed 1.0, yet many published studies report this inconsistency. We teach and believe, based on differential equation derivations, that rate of absorption has no influence on measured systemic clearance following an oral dose, i.e., determined as available dose divided by AUC. Previously, it was thought that any difference in calculating F from urine data versus that from systemic concentration AUC data was due to the inability to accurately measure urine data. A PubMed literature search for drugs exhibiting F>1.0 and studies for which F was measured using both AUC and urinary excretion dose corrected analyses yielded data for 35 drugs. We show and explain, using Kirchhoff’s Laws, that these universally held concepts concerning bioavailability may not be valid. Bioavailability, determined using systemic concentration measurements, for many drugs may be overestimated since AUC reflects not only systemic elimination but also absorption rate characteristics, which is most easily seen for renal clearance measures. Clearance of drug from the absorption site must be significantly greater than clearance following an iv bolus dose for F(AUC) to correctly correspond with F(urine). The primary purpose of my presentation is to demonstrate that studies resulting in F>1.0 and/or greater systemic vs urine bioavailability predictions may be accurate. Importantly, these explications have no significant impact on current regulatory guidance for bioequivalence testing, nor on the use of exposure (AUC) measures in making drug dosing decisions.

Dr. Benet, Professor and former Chairman (1978-1998) of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco (UCSF), received his AB, BS and MS from the University of Michigan, and PhD from UCSF. He has received nine honorary doctorates, five from Europe and four from the US, most recently the University of Lisbon in 2016. Dr. Benet served as President of the Academy of Pharmaceutical Sciences (1985) and as the founder and first President of the American Association of Pharmaceutical Scientists (1986). In 1987 he was elected to membership in the National Academy of Medicine of the US National Academy of Sciences. He previously served as the Treasurer of ISSX, Chair of the Drug Metabolism Gordon Conference, and in 2015 received the ISSX North American Achievement Award. In May of this year, he received the Lifetime Achievement award of the Frankfurt Foundation Quality of Medicines. Dr. Benet has published over 620 scientific articles and book chapters, holds 12 patents and served as editor of 7 books. He has been among the most highly cited pharmacologists worldwide with Clarivate Analytics listing over 33,000 citations and Google Scholar more than 51,000 citations.