title: 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 (Fa) and intestinal availability (Fg) are independently determined by the apical membrane permeation and intestinal metabolism, respectively. However, the validity of this belief has not been well discussed, and Fa and Fg are often used without careful definition. In this review, Fa and Fg 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 Fa and Fg, whereas apical efflux transporters including P-glycoprotein had no influence on Fg at least under the linear condition. To determine whether Fa and Fg calculated using different clinical methods are identical, empirical Fa and Fg were mathematically described based on "feces method" and "grapefruit juice method" and compared with their definitions. Fa and Fg obtained by the feces method corresponded with their definitions whereas the grapefruit juice method provided smaller Fa and larger Fg 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 Fa and Fg should be considered when we intend to separately determine these values.
authors: DMPK Research Laboratory, Watarase Research Center, Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan. Electronic address: yuuta.tanaka@mb.kyorin-pharm.co.jp.
authors: Yuta
authors: Y
authors: Tanaka
authors: DMPK Research Laboratory, Watarase Research Center, Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan.
authors: Yoshiaki
authors: Y
authors: Kitamura
authors: Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors: Kazuya
authors: K
authors: Maeda
authors: Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Research Cluster for Innovation, Yokohama, Japan.
authors: Yuichi
authors: Y
authors: Sugiyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008962:Models, Theoretical; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A
keywords: ABC transporters; intestinal absorption; intestinal metabolism; mathematical model; passive diffusion/transport