Hepatobiliary transporters in drug-induced cholestasis: a perspective on the current identifying tools.

INTRODUCTION: Impaired bile formation leads to the accumulation of cytotoxic bile salts in hepatocytes and, consequently, cholestasis and severe liver disease. Knowledge of the role of hepatobiliary transporters, especially the bile salt export pump (BSEP), in the pathogenesis of cholestasis is continuously increasing. AREAS COVERED: This review provides an introduction into the role of these transport proteins in bile formation. It addresses the clinical relevance and pathophysiologic consequences of altered functions of these transporters by genetic mutations and drugs. In particular, the current practical aspects of identification and mitigation of drug candidates with liver liabilities employed during drug development, with an emphasis on preclinical screening for BSEP interaction, are discussed. EXPERT OPINION: Within the potential pathogenetic mechanisms of acquired cholestasis, the inhibition of BSEP by drugs is well established. Interference of a new compound with BSEP transport activity should raise a warning sign to conduct follow-up experiments and to monitor liver function during clinical development. A combination of in vitro screening for transport interaction, in silico predicting models, and consideration of physicochemical and metabolic properties should lead to a more efficient screening of potential liver liability.

Botanical-drug interactions: a scientific perspective.

There is a continued predisposition of concurrent use of drugs and botanical products. A general lack of knowledge of the interaction potential together with an under-reporting of botanical use poses a challenge for the health care providers and a safety concern for patients. Botanical-drug interactions increase the patient risk, especially with regard to drugs with a narrow therapeutic index (e.g., warfarin, cyclosporine, and digoxin). Examples of case reports and clinical studies evaluating botanical-drug interactions of commonly used botanicals in the US are presented. The potential pharmacokinetic and pharmacodynamic bases of such interactions are discussed, as well as the challenges associated with the interpretation of the available data and prediction of botanical-drug interactions. Recent FDA experiences with botanical products and interactions including labeling implications as a risk management strategy are highlighted.

Comparison of the estrogenic potencies of standardized soy extracts by immature rat uterotrophic bioassay.

Soy phytoestrogens, isoflavones, are a primary class of plant-based estrogen alternatives being sold over the counter nowadays. Genistein, daidzein and glycitein are the major isoflavones found in soybeans, as aglycones and glycosides. Each isoflavone shows distinctive estrogenic activity and pharmacokinetics. Soy dry extracts, employed as pharmaceutical raw material for manufacturing isoflavone supplements, are standardized to contain 40% of total isoflavones, but the amount of each isoflavone is highly diverse. The influence of these compositional differences on the estrogenic potency of soy extracts was evaluated by uterotrophic bioassay. Five commercial samples of standardized soy dry extract, homogeneously suspended in arachis oil, were administered per os in serial doses (125-4150 mg/kg bw/day) to immature female rats for 3 days. Soy extract samples with considerable diversity in isoflavone composition revealed different estrogenic potencies. Our results indicate a need of standardization of the individual isoflavone content in soy extracts.