Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Abstract

Objectives This review provides an overview of intestinal human transporters for organic anions and stresses the need for standardization of the various in‐vitro methods presently employed in drug–drug interaction (DDI) investigations. Key findings Current knowledge on the intestinal expression of the apical sodium‐dependent bile acid transporter (ASBT), the breast cancer resistance protein (BCRP), the monocarboxylate transporters (MCT) 1, MCT3‐5, the multidrug resistance associated proteins (MRP) 1–6, the organic anion transporting polypetides (OATP) 2B1, 1A2, 3A1 and 4A1, and the organic solute transporter α/β (OSTα/β) has been covered along with an overview of their substrates and inhibitors. Furthermore, the many challenges in predicting clinically relevant DDIs from in‐vitro studies have been discussed with focus on intestinal transporters and the various methods for deducting in‐vitro parameters for transporters (Km/Ki/IC50, efflux ratio). The applicability of using a cut‐off value (estimated based on the intestinal drug concentration divided by the Ki or IC50) has also been considered. Summary A re‐evaluation of the current approaches for the prediction of DDIs is necessary when considering the involvement of other transporters than P‐glycoprotein. Moreover, the interplay between various processes that a drug is subject to in‐vivo such as translocation by several transporters and dissolution should be considered.

Intestinal transport and metabolism of bile acids

“…Several OATPs capable of transporting bile acids are expressed in the small intestine (OATP1A2 and OATP2B1 in humans; Oatp1a4, Oatp1a5, and Oatp2b1 in mice) ( 48,49 ), and their role in transporting xenobiotics and endobiotics such as bile acids has been examined recently using OATP-null mouse models ( 13, 50 ). In mice engineered to delete the entire Oatp1a/ 1b locus (encompassing Slco1b2 , Slco1a4 , Slco1a1 , Slco1a6 , and Slco1a5 ), plasma levels of conjugated bile acids were unchanged, whereas unconjugated bile acid levels increased by approximately 13-fold ( 13 ).…”

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

“…An elementary consequence of standard enzyme kinetics is that molecules using the same protein may compete with or inhibit each other, in this case each other's transport. This is a simply vast topic, so (notwithstanding earlier critiques of summarizing via the enormous review literature), we here simply point out several useful and recent reviews (from the last 3 years only) that describe in detail the many named and genetically identified transporters that are involved in DDI (Han, 2011; Kido et al, 2011; Klatt et al, 2011; König, 2011; Maeda et al, 2011; Marzolini et al, 2011; Müller and Fromm, 2011; Riches et al, 2011; Shitara, 2011; Zhang et al, 2011b; Bi et al, 2012; Elsby et al, 2012; Feng et al, 2012, 2013, 2014; Fromm, 2012; Grandvuinet et al, 2012; Karlgren et al, 2012; Keogh, 2012; Lepist and Ray, 2012; Nies et al, 2012; Sissung et al, 2012; Sprowl and Sparreboom, 2012, 2014; Takanohashi et al, 2012; Varma et al, 2012; Yeo et al, 2012, 2013; Yoshida et al, 2012, 2013; Kis et al, 2013; König et al, 2013; Maeda and Sugiyama, 2013; Sugiyama and Steffansen, 2013; Tang et al, 2013; Zamek-Gliszczynski et al, 2013; Goswami et al, 2014; Tannenbaum and Sheehan, 2014; Vildhede et al, 2014). We are not aware of any papers that showed such DDI based on any measured competition for transport via the phospholipid bilayer.…”

Sodium-dependent bile salt transporters of the SLC10A transporter family: more than solute transporters

“…In addition, inhibitors of ASBT (A3309 & 264W94) have been shown to produce beneficial effects in patients with chronic idiopathic constipation (27,144) and alleviate diabetes in Zucker Diabetic Fatty (ZDF) rats (26). A number of drugs have been shown to inhibit ABST (40,54,172) and these include calcium channel blockers (nifedipine, isradipine, diltiazem, verapamil), HMG-CoA reductase inhibitors (simvastatin, mevastatin, lovastatin), diuretics (spironolactone, bumetadine, althazide, but not furosemide) and others (dibucaine, indomethacin, mesoridazine, quinine). However, the clinical implications of inhibition of ASBT by these drugs are yet to be determined.…”