title: Quantitative prediction of intestinal metabolism in humans from a simplified intestinal availability model and empirical scaling factor.
abstract: This study aimed to establish a practical and convenient method of predicting intestinal availability (F(g)) in humans for highly permeable compounds at the drug discovery stage, with a focus on CYP3A4-mediated metabolism. We constructed a "simplified F(g) model," described using only metabolic parameters, assuming that passive diffusion is dominant when permeability is high and that the effect of transporters in epithelial cells is negligible. Five substrates for CYP3A4 (alprazolam, amlodipine, clonazepam, midazolam, and nifedipine) and four for both CYP3A4 and P-glycoprotein (P-gp) (nicardipine, quinidine, tacrolimus, and verapamil) were used as model compounds. Observed fraction of drug absorbed (F(a)F(g)) values for these compounds were calculated from in vivo pharmacokinetic (PK) parameters, whereas in vitro intestinal intrinsic clearance (CL(int,intestine)) was determined using human intestinal microsomes. The CL(int,intestine) for the model compounds corrected with that of midazolam was defined as CL(m,index) and incorporated into a simplified F(g) model with empirical scaling factor. Regardless of whether the compound was a P-gp substrate, the F(a)F(g) could be reasonably fitted by the simplified F(g) model, and the value of the empirical scaling factor was well estimated. These results suggest that the effects of P-gp on F(a) and F(g) are substantially minor, at least in the case of highly permeable compounds. Furthermore, liver intrinsic clearance (CL(int,liver)) can be used as a surrogate index of intestinal metabolism based on the relationship between CL(int,liver) and CL(m,index). F(g) can be easily predicted using a simplified F(g) model with the empirical scaling factor, enabling more confident selection of drug candidates with desirable PK profiles in humans.
authors.affiliation: Analysis and Pharmacokinetics Research Laboratories, Discovery Drug Metabolism and Pharmacokinetics, Astellas Pharma Inc., Tsukuba-shi, Ibaraki 305-8585, Japan. keitarou.kadono@jp.astellas.com
authors.forename: Keitaro
authors.initials: K
authors.lastname: Kadono
authors.forename: Takafumi
authors.initials: T
authors.lastname: Akabane
authors.forename: Kenji
authors.initials: K
authors.lastname: Tabata
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Gato
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Terashita
authors.forename: Toshio
authors.initials: T
authors.lastname: Teramura
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005544:Forecasting / Q000379:methods*; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism; D008962:Models, Theoretical; D010539:Permeability; D010599:Pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human