Combination of the in vitro models that are high throughput but less predictive and the in vivo models that are low throughput but more predictive is used effectively to evaluate the intestinal permeability and transport characteristics of a large number of drug candidates during lead selection and lead optimization processes. Parallel artificial membrane permeability assay and Caco-2 cells are the most frequently used in vitro models to assess intestinal permeability. The popularity of these models stems from their potential for high throughput, cost effectiveness, and adequate predictability of absorption potential in humans. However, several caveats associated with these models (eg, poor predictability for transporter-mediated and paracellularly absorbed compounds, significant nonspecific binding to cells/devices leading to poor recovery, variability associated with experimental factors) need to be considered carefully to realize their full potential. P-glycoprotein, among other pharmaceutically relevant transporters, has been well demonstrated to be the major determinant of drug disposition. The review article presents an objective analysis of the permeability and transporter models currently being used in the pharmaceutical industry and could help guide the discovery scientists in implementing these models in an optimal fashion.

17alpha-Ethinylestradiol (EE) is widely used as the estrogenic component of oral contraceptives (OC). In vitro and in vivo metabolism studies indicate that EE is extensively metabolised, primarily via intestinal sulfation and hepatic oxidation, glucuronidation and sulfation. Cytochrome P450 (CYP)3A4-mediated EE 2-hydroxylation is the major pathway of oxidative metabolism of EE. For some time it has been known that inducers of drug-metabolising enzymes (such as the CYP3A4 inducer rifampicin [rifampin]) can lead to breakthrough bleeding and contraceptive failure. Conversely, inhibitors of drug-metabolising enzymes can give rise to elevated EE plasma concentrations and increased risks of vascular disease and hypertension. In vitro studies have also shown that EE inhibits a number of human CYP enzymes, such as CYP2C19, CYP3A4 and CYP2B6. Consequently, there are numerous reports in the literature describing EE-containing OC formulations as perpetrators of pharmacokinetic drug interactions. Because EE may participate in multiple pharmacokinetic drug interactions as either a victim or perpetrator, pharmaceutical companies routinely conduct clinical drug interaction studies with EE-containing OCs when evaluating new chemical entities in development. It is therefore critical to understand the mechanisms underlying these drug interactions. Such an understanding can enable the interpretation of clinical data and lead to a greater appreciation of the profile of the drug by physicians, clinicians and regulators. This article summarises what is known of the drug-metabolising enzymes and transporters governing the metabolism, disposition and excretion of EE. An effort is made to relate this information to known clinical drug-drug interactions. The inhibition and induction of drug-metabolising enzymes by EE is also reviewed.

Organic anion-transporting polypeptides (OATP) 1B1, 1B3, and 2B1 can serve as the loci of drug-drug interactions (DDIs). In the present work, the cynomolgus monkey was evaluated as a potential model for studying OATP-mediated DDIs. Three cynomolgus monkey OATPs (cOATPs), with a high degree of amino acid sequence identity (91.9, 93.5, and 96.6% for OATP1B1, 1B3, and 2B1, respectively) to their human counterparts, were cloned, expressed, and characterized. The cOATPs were stably transfected in human embryonic kidney cells and were functionally similar to the corresponding human OATPs (hOATPs), as evident from the similar uptake rate of typical substrates (estradiol-17b-D-glucuronide, cholecystokinin octapeptide, and estrone-3-sulfate). Moreover, six known hOATP inhibitors exhibited similar IC 50 values against cOATPs. To further evaluate the appropriateness of the cynomolgus monkey as a model, a known hOATP substrate [rosuvastatin (RSV)]-inhibitor [rifampicin (RIF)] pair was examined in vitro; the monkey-derived parameters (RSV K m and RIF IC 50 ) were similar (within 3.5-fold) to those obtained with hOATPs and human primary hepatocytes. In vivo, the area under the plasma concentration-time curve of RSV (3 mg/kg, oral) given 1 hour after a single RIF dose (15 mg/kg, oral) was increased 2.9-fold in cynomolgus monkeys, consistent with the value (3.0-fold) reported in humans. A number of in vitro-in vivo extrapolation approaches, considering the fraction of the pathways affected and free versus total inhibitor concentrations, were also explored. It is concluded that the cynomolgus monkey has the potential to serve as a useful model for the assessment of OATP-mediated DDIs in a nonclinical setting. IntroductionDrug-drug interactions (DDIs) have often been attributed to cytochrome P450 (P450) enzymes because of their prominent role in the metabolic clearance of drugs (Vuppugalla et al., 2010). More recently, however, attention has turned to active transport processes in different organs and the close interplay between drug transport and metabolism at the cellular level. In particular, organic anion-transporting polypeptides (OATPs) are known to mediate the active uptake of numerous drugs into hepatocytes and hence govern their overall clearance, pharmacokinetic profile, and liver-toplasma ratio (Giacomini et al., 2010;Fenner et al., 2012;Yoshida et al., 2012).OATPs can also serve as the loci of important DDIs leading to changes in systemic and local drug concentrations, possibly resulting in altered efficacy and enhanced toxicity (Giacomini et al., 2010;Yoshida et al., 2012). For example, cyclosporine A (CsA) increases the area under the concentration-time curve (AUC) (∼15-fold) and C max (∼14-fold) of atorvastatin in s This article has supplemental material available at jpet.aspetjournals.org.ABBREVIATIONS: AUC, area under the concentration-time curve; CCK-8, cholecystokinin octapeptide; CI, confidence interval; cOATP, cynomolgus organic anion-transporting polypeptide; CsA, cyclosporine A; DDI, drug-drug inter...