No abstract

In clinical, patients usually take many kinds of drugs at the same time. Thus, drug-drug interactions involving transporters can often directly affect the therapeutic safety and efficacy of many drugs. However, there have been few studies on food-drug interactions involving transporters. Dietary polyphenols have been widely assumed to be beneficial to human health. Polyphenols are commercially prepared and used as functional foods. We report here for the first time that ferulic acid, which is widely used as a functional food, affects the transport of clinical agents. It is important to be aware of the potential of food-drug interactions and to act in order to prevent undesirable and harmful clinical consequences.

Direct oral anticoagulants, like apixaban and rivaroxaban, are important for the treatment and prophylaxis of venous thromboembolism and to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Since apixaban and rivaroxaban are predominantly eliminated by CYP3A and P-glycoprotein (P-gp), concomitant use of combined P-gp and strong CYP3A4 inhibitors and inducers should be avoided. Physiologically-based pharmacokinetic (PBPK) models for apixaban and rivaroxaban were developed to estimate the net effect of CYP3A induction, P-gp inhibition and P-gp induction by rifampicin. The disposition of rivaroxaban is more complex compared to apixaban since both hepatic and renal P-gp is considered to contribute to rivaroxaban elimination. Furthermore, organic anion transporter-3 (OAT3), a renal uptake transporter, may also contribute the elimination of rivaroxaban from systemic circulation. The models were verified with observed clinical drug-drug interactions with CYP3A and P-gp inhibitors. With the developed models, the predicted AUC and C max ratios were 0.43 and 0.48, respectively, for apixaban, and 0.50 to 0.52 and 0.72 to 0.73, respectively, for rivaroxaban when co-administered with 600 mg multiple dose of rifampicin and which were very close to observed data. The impact of each of the elimination pathways was assessed for rivaroxaban and inhibition of CYP3A led to a larger impact over intestinal and hepatic P-gp. Inhibition of renal OAT3 or P-gp led to an overall modest interaction. The developed apixaban and rivaroxaban models can be further applied to the investigation of interaction with other P-gp and/or CYP3A4 inhibitors and inducers.

Nateglinide, a novel oral hypoglycemic agent, rapidly reaches its maximum serum concentration after oral administration, suggesting that it is rapidly absorbed in the intestine. However, nateglinide itself is not transported by MCT1 or PEPT1. The aim of this study was to characterize the transporters on the apical side of the small intestine that are responsible for the rapid absorption of nateglinide. It has been reported that the uptake of fluorescein by Caco-2 cells occurs via an H+-driven transporter and that the intestinal fluorescein transporter is probably not MCT1. We examined the contribution of the fluorescein transporter to the uptake of nateglinide by Caco-2 cells. Fluorescein competitively inhibited H+-dependent nateglinide uptake. All of fluorescein transporter inhibitors examined reduced the uptake of nateglinide. Furthermore, nateglinide inhibited fluorescein uptake. We conclude that the intestinal nateglinide/H+ cotransport system is identical to the intestinal fluorescein/H+ cotransport system.

The effectiveness of several basic compounds for testing silica-based stationary phases was reviewed by applying them to recent columns for reversed-phase HPLC. Most octadecylsilylated (C18) stationary phases, prepared as a base-deactivated material from high-purity silica gel with endcapping, provided excellent peak shape and column efficiency for the bases including benzylamine and amitriptyline that once caused problems and were subsequently employed for testing silanol activities. However, a cyclic tertiary amine, dextrometorphan, was eluted as an acceptable peak from only a few columns at neutral pH. Such a more sensitive probe is expected to contribute to further improvement of the stationary phase for reversed-phase HPLC.