Explication of Definitional Description and Empirical Use of Fraction of Orally Administered Drugs Absorbed From the Intestine (Fa) and Intestinal Availability (Fg): Effect of P-glycoprotein and CYP3A on Fa and Fg.

Abstract Conventionally, it is believed that the fraction of orally administered drugs absorbed from the intestine (F a ) and intestinal availability (F g ) are independently determined by the apical membrane permeation and intestinal metabolism, respectively. However, the validity of this belief has not been well discussed, and F a and F g are often used without careful definition. In this review, F a and F g are mathematically described based on their definitions under the linear kinetics of metabolism and transport. Even considering with different models, intestinal metabolic enzymes such as cytochrome P450 3A affected both F a and F g , whereas apical efflux transporters including P-glycoprotein had no influence on F g at least under the linear condition. To determine whether F a and F g calculated using different clinical methods are identical, empirical F a and F g were mathematically described based on “feces method” and “grapefruit juice method” and compared with their definitions. F a and F g obtained by the feces method corresponded with their definitions whereas the grapefruit juice method provided smaller F a and larger F g particularly for dual substrates of P-glycoprotein and cytochrome P450 3A with low membrane permeability. Our analyses suggest that the definitions and calculation methods of F a and F g should be considered when we intend to separately determine these values.