Drug Metabolism and Drug Interactions最新文献

Human carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) are serine esterases responsible for the hydrolysis of ester and amide bonds present in a number of pharmaceutical products. Several common genetic variants of the CES1 and CES2 genes have been shown to influence drug metabolism and clinical outcomes. Polymorphisms of the CES1 gene have been reported to affect the metabolism of dabigatran etexilate, methylphenidate, oseltamivir, imidapril, and clopidogrel, whereas variants of the CES2 gene have been found to affect aspirin and irinotecan. Although the findings of these studies may be preliminary, they demonstrate the potential clinical utility of CES polymorphisms; however, more research is required, especially with respect to CES2. In this review, we outline the functional, molecular, and genetic properties of CES1 and CES2, and highlight recent studies that have shown relations between CES1 and CES2 variants and contemporary pharmacotherapy.

Background: Most identified drug transporters belong to the ATP-binding cassette (ABC) and solute carrier (SLC) families. Recent research indicates that these transporters play an important role in the absorption, distribution and excretion of drugs, and are involved in clinically relevant drug-drug interactions for systemic drugs. However, very little is known about the role of drug transporters in human skin, especially in the disposition of topically applied drugs, and their involvement in drug-drug interactions. The aim of this work was to characterize the ABC transporters in human skin.

Methods: Expressions of ABCB1 multidrug resistance protein 1 (MDR1) also known as P-gp, ABCC1 and ABCC2 multidrug resistance-associated protein 1 and 2 (MRP1 and MRP2), and ABCG2 brest cancer resistance protein (BCRP) in human skin tissues were analyzed by quantitative real-time polymerase chain reaction (RT-PCR). The modulations of ABCB1 and ABCC1 expressions were analyzed after ex vivo treatment of human skin with rifampicin and dexamethasone. The localization of the major transporter MRP1 in human skin was analyzed by immunohistochemistry. Finally, functional analysis of MRP1 in human skin was performed using different specific substrates and inhibitors.

Results: The expressions of ABCB1, ABCC1, ABCC2, and ABCG2 were all detected in human skin, of which the expression of ABCC1 was considered the most important. The comparison of human skin with human hepatocytes and kidneys shows that the expression of ABCC1 increased 15-fold in skin than in hepatocytes. Immunohistochemistry revealed marked expressions of MRP1 within the hair follicle, sweat gland and muscle, as well as moderate expression in the basal epidermis. Functional analysis demonstrated that the skin absorptions of rhodamine 123, [3H]-vinblastine, and [3H]-LTC4 were markedly decreased in the presence of MRP1 inhibitors (verapamil and MK571), thus supporting the role of MRP1 in the uptake of compounds from the epidermal compartment as well as their secretion into the bloodstream and sweat ducts.

Conclusions: The present findings are the first to demonstrate the involvement of MRP1 in drug uptake in human skin.

Background: This was a randomized, open-label, three-way crossover study to assess the effects of AST-120 (an orally administered spherical carbon adsorbent acting in the gastrointestinal tract without systemic circulation) on the single-dose pharmacokinetics of metoprolol in an extended-release formulation (metoprolol ER) in healthy volunteers.

Methods: A total of 34 subjects were singly administered metoprolol ER alone (A), and metoprolol ER in combination with AST-120 simultaneously (B) and 1 h later (C).

Results: The total exposure was more significantly reduced in both treatments B and C than that in treatment A; the geometric mean ratios of area under the curve extrapolated to infinity (AUC0-∞) for B/A and C/A were reduced by approximately 30% in both treatments B and C. Maximum observed plasma concentration (Cmax) of metoprolol in treatment B significantly decreased, whereas Cmax in treatment C was slightly decreased. AST-120 treatment was unlikely to affect apparent first-order terminal elimination half-life (T1/2) of metoprolol significantly. Reduction in heart rate and blood pressure readings were similar across the treatment periods. Coadministration of AST-120 and metoprolol ER was safe and was well tolerated.

Conclusions: Because AST-120 reduced gastrointestinal absorption of metoprolol ER, careful monitoring of heart rate and blood pressure is recommended in coadministration of AST-120 with metoprolol ER.

The potential pharmacokinetic interactions between macromolecules and small-molecule drugs have received more and more attention with the increasing development of macromolecule therapeutics. Studies have shown that cytokines can differentially modulate drug-metabolizing enzymes and transporters, which raises concerns on the potential interactions of therapeutic cytokines and cytokine modulators on the disposition of small-molecule drugs. Although many in vitro studies have been conducted to characterize the effects of cytokines on drug-metabolizing enzymes and transporters, these studies were limited to only a handful of cytokines, such as interleukin-1 (IL-1), IL-6, tumor necrosis factor-α, and interferon. It is also challenging to translate these in vitro results to in vivo. In addition, information on the impact of cytokine modulators on drug-metabolizing enzymes and transporters is rather limited. More research is needed in this area. The present review is to provide a summary of the in vitro findings on the pharmacokinetic interactions of therapeutic cytokines and cytokine modulators on small-molecule drugs. Discussion on current challenges in assessing these interactions is also included.