Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption

Abstract

The ability to predict drug disposition involves concurrent consideration of many chemical and physiological variables and the effect of food on the rate and extent of availability adds further complexity due to postprandial changes in the gastrointestinal (GI) tract. A system that allows for the assessment of the multivariate interplay occurring following administration of an oral dose, in the presence or absence of meal, would greatly benefit the early stages of drug development. This is particularly true in an era when the majority of new molecular entities are highly permeable, poorly soluble, extensively metabolized compounds (BDDCS Class 2), which present the most complicated relationship in defining the impact of transporters due to the marked effects of transporter-enzyme interplay. This review evaluates the GI luminal environment by taking into account the absorption/transport/elimination interplay and evaluates the physiochemical property issues by taking into account the importance of solubility, permeability and metabolism. We concentrate on the BDDCS and its utility in predicting drug disposition. Furthermore, we focus on the effect of food on the extent of drug availability (F), which appears to follow closely what might be expected if a significant effect of high fat meals is inhibition of transporters. That is, high fat meals and lipidic excipients would be expected to have little effect on F for Class 1 drugs; they would increase F of Class 2 drugs, while decreasing F for Class 3 drugs.

Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance

“…Drug transporters, such as oatp2 and mdr1 (P-gp), play an important role in xenobiotic clearance as a necessary step before phase I metabolism (31,32). Both drug transport and metabolism are known to be affected by the activities of co-administered drugs or dietary supplements with potentially disastrous consequences (32,33). To demonstrate that oxygenated co-cultures can detect these drug-drug interactions we quantified the clearance of midazolam and digoxin in the presence of 100 M of the oatp2 inhibitor rifampicin (31) or in the presence of 200 M of the grapefruit flavonoid naringenin, a CYP3A4 and P-gp inhibitor (34)(35)(36).…”

Food and Drug Interactions: A General Review

“…The investigation of the effects of drug transporters on drug disposition has been continued for many years [Custodio et al 2008]. The oral administration of drugs to patients is convenient, practical, and preferred for many reasons.…”

Evaluation of CYP3A activity in humans using three different parameters based on endogenous cortisol metabolism

“…Second, according to a previous study, the efflux of P-glycoprotein (P-gp) in vivo probably affects AUC F [15] . However, as MDZ exhibits characteristics of a class 1 drug in the biopharmaceutical classification system, the disposition of MDZ is influenced to a lesser degree by P-gp [16,17] . Additionally, differences in renal function in different subjects may cause heterogeneity in 6β-OHF excretion that could affect the values of Cl m(6β) .…”