3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, commonly known as statins, may possess cancer preventive and therapeutic properties. Statins are effective suppressors of cholesterol synthesis with a well-established risk-benefit ratio in cardiovascular disease prevention. Mechanistically, targeting HMGCR activity primarily influences cholesterol biosynthesis and prenylation ...

17alpha-Ethinylestradiol (EE2), a component of oral contraceptives, is known to undergo considerable first-pass 3-O-sulfation in the intestine and liver. Once formed, the 3-O-sulfate conjugate (EE2-Sul) is detected in circulation at appreciable levels (versus parent EE2) and is present in bile. Therefore, hepatic uptake of EE2-Sul was assessed with suspensions of cryopreserved human primary hep...

Purpose:Organic anion-transporting polypeptide (OATP) drug uptake transporters are thought to play an important role in drug pharmacokinetics and toxicokinetics. We aimed to determine the influence of the individual human OATP1B1, OATP1B3, and OATP1A2 transporters on the in vivo disposition of the anticancer drugs methotrexate and paclitaxel by using liver-specific humanized OATP1A/1B transgeni...

Analogs of the cyclic nucleotides cAMP and cGMP have been extensively used to mimic or modulate cellular events mediated by protein kinase A (PKA), Exchange protein directly activated by cAMP (Epac), or protein kinase G (PKG). We report here that some of the most commonly used cyclic nucleotide analogs inhibit transmembrane transport mediated by the liver specific organic anion transporter pept...

The glucuronide conjugate of methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate (S-8921; S-8921G) is a 6000-fold more potent inhibitor of an ileal apical sodium-dependent bile acid transporter (SLC10A2) than S-8921 and is responsible for the hypocholesterolemic effect of S-8921 in rats. Because S-8921G is formed in the intestine and liver, the present stud...

Chronic treatment of methicillin-resistant Staphylococcus aureus strains with the bacteriostatic agent fusidic acid (FA) is frequently associated with myopathy including rhabdomyolysis upon coadministration with statins. Because adverse effects with statins are usually the result of drug-drug interactions, we evaluated the inhibitory effects of FA against human CYP3A4 and clinically relevant dr...

Typically, pharmacokinetic-pharmacodynamic (PK/PD) models use plasma concentration as the input that drives the PD model. However, interindividual variability in uptake transporter activity can lead to variable drug concentrations in plasma without discernible impact on the effect site organ concentration. A physiologically based PK/PD model for rosuvastatin was developed that linked the predic...