Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs

Abstract

Nobody doubts the importance of organic anion transporting polypeptide (OATP)1B1 and 1B3 in the clinical pharmacokinetics of substrate drugs. Based on the theory of pharmacokinetics, even if a drug is eliminated from the body by extensive metabolism, the rate-determining process of the hepatic intrinsic clearance of OATP substrates is often hepatic uptake. Because of their broad substrate specificities, once the functions of OATP1B1 or OATP1B3 are altered by several kinds of special occasions such as drug-drug interactions (DDI) and genetic polymorphisms of transporter genes, the hepatic clearance of many kinds of structurally-unrelated drugs is expected to be changed. In some cases, these alterations of pharmacokinetics lead to modified pharmacological effects and adverse reactions such as statin-induced myotoxicity and the glucose-lowering effect of anti-diabetes drugs. Thus, appropriate methods with which to quantitatively predict the changes in plasma and tissue concentrations of drugs are needed in the process of drug development. As for DDI, a static model that takes into consideration of the theoretically-maximum unbound inhibitor concentration is often used for the sensitive detection of possible DDI risks and this method has been adopted in several regulatory guidance/guidelines on DDI. Regarding genetic polymorphisms, the effects of SLCO1B1 c.388A>G and c.521T>C on the pharmacokinetics of substrate drugs have been extensively investigated. Even though there are some discrepancies, c.521T>C generally decreased hepatic uptake activity, while c.388A>G tended to slightly increase it. This article briefly summarizes the current status of research on hepatic OATP1B1 and OATP1B3 and the clinical significance of their functions.

Transport vs. Metabolism: What Determines the Pharmacokinetics and Pharmacodynamics of Drugs? Insights From the Extended Clearance Model

“…SNPs). Indeed, patients with the OATP1B1 polymorphism c.521T>C had no change in their LDL cholesterol lowering effect of ATV even though there was a 1.6–2.5-fold increase in plasma ATV AUC (6). But, while ATV PD effect is not affected, higher systemic concentrations of ATV may lead to off-target toxicity, such as muscle myopathy.…”

The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers

“…However, blocking the function of these two liver-specific OATPs can change the hepatic clearance of drugs, which can result in their altered pharmacokinetics (i.e., elevated plasma levels of drugs are usually expected). This may cause serious adverse reactions, such as statin-induced myotoxicity, as has been demonstrated by co-administration of cyclosporine-A and gemfibrozil with statins (for review, see Kalliokoski and Niemi, 2009; Maeda, 2015). …”

A Clinical Quantitative Evaluation of Hepatobiliary Transport of [11C]Dehydropravastatin in Humans Using Positron Emission Tomography

“…The plasma concentrations of some drugs, the hepatic uptake of which is the rate-determining process, are not appropriate indices for assessing the changes in canalicular efflux transporters. Under such conditions, changes in the canalicular efflux transporters hardly affects the intrinsic clearance for the overall hepatic elimination, whereas liver concentrations are more profoundly altered than the plasma concentrations, depending on the changes (Watanabe et al, 2010;Maeda, 2015).…”