Quantitative Prediction of Intestinal Metabolism in Humans from a Simplified Intestinal Availability Model and Empirical Scaling Factor

Abstract

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.Given the substantial time and cost associated with drug discovery and development, increasing importance has been placed on the prediction of pharmacokinetics (PK) in humans of drug candidates at the discovery stage to avoid later termination of development because of an undesirable PK profile. Bioavailability (F) of an orally administered drug, which is the fraction of drug reaching systemic blood circulation, is expressed as the product of the fraction of the dose that enters the enterocyte (F a ), intestinal availability (F g ), and hepatic availability (F h ). Therefore, to effectively pass into systemic blood circulation, orally administered drugs must not only have high solubility and permeability in the gastrointestinal tract but also be stable against metabolizing enzymes in the gastrointestinal tract and liver.At the drug discovery stage, compounds selected as drug candidates using high-throughput screening typically are those with high permeability because intestinal permeability is one of the most important factors in determining the F of orally administered drugs. Although P-glycoprotein (P-gp) is highly expressed in intestinal epithelial cells and has the potential to reduce drug absorption, the effect on drug absorption is not qu...

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and QGutModel

“…3 and 4) revealed the blunting effect due to drug reabsorption, or the factor (1-F abs ), where F abs or fraction absorbed is k a /(k a ϩ k g ) [where k g is the luminal degradation constant that comprises gastrointestinal transit and degradation] (Lin et al, 1999;Pang, 2009, 2010). The F abs term has been reported to be highly correlated to the permeability of drug, P app (Zhu et al, 2002;Corti et al, 2006;Kadono et al, 2010). Apical secretion mediated via the CL int,sec,I was nullified when the fraction absorbed ϳ1, rendering the conclusion that F I is affected more by CL int,met,I and not so much by CL int,sec,I Pang, 2009, 2010;Chow and Pang, 2013).…”

Quantitative Prediction of Human Intestinal Glucuronidation Effects on Intestinal Availability of UDP-Glucuronosyltransferase Substrates Using In Vitro Data

“…P app values are summarized in Table 5. A high F a can be expected when the P app value is greater than 1.0 ϫ 10 Ϫ6 cm/s (Kadono et al, 2010), which was seen in all 11 substrates except for quercetin and gemfibrozil.…”

“…Kadono et al (2010) simplified eq. 9 for highly permeable compounds assuming PS inf Ͼ Ͼ Q, PS inf Ͼ Ͼ PS eff and CL ab ϭ constant, to give the following (eq.…”

“…Because F a F g depends on Q h , three different reference values (17.1, 20.7, and 25.5 ml ⅐ min Ϫ1 ⅐ kg Ϫ1 ) were used (Davies and Morris, 1993;Kadono et al, 2010). Pharmacokinetic parameters were derived from the literature.…”

“…One method is the simplified intestinal availability (SIA) model (Kadono et al, 2010), which predicts human F a F g from in vitro data for highly permeable CYP3A4 substrates as shown in eq. 1:…”