Abstract:The organic anion transporting polypeptide 1A2 (OATP1A2), a membrane drug transporter expressed on important organs (such as the brain, kidney, and intestine) may be a key element in the disposition of drugs. Previous studies demonstrated that it could transport a broad spectrum of substrates, including endogenous molecules and clinically relevant drugs, such as several b-blockers and 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors. The primary objective of this study was to investigate OATP1A2 transport a… Show more
“…Following removal of preincubation solution, 400 ml of HBSS supplemented with 10 mM HEPES (OATP1B1 only) or DPBS containing ronacaleret at the previously listed target concentrations and 1 mM (OATP1B1, OATP1B3, and OATP2B1) or 5 mM (OATP1A2) rosuvastatin was added to the wells in triplicate. Rosuvastatin substrate concentrations for these transporters in the present study were lower than the published K m values (van de Steeg et al, 2013;Bosgra et al, 2014;Lu et al, 2015). Cells were incubated at 37°C for 3 minutes for OATP1B1, OATP1B3, and OATP1A2 and for 10 minutes for OATP2B1.…”
Rosuvastatin is a widely prescribed antihyperlipidemic which undergoes limited metabolism, but is an in vitro substrate of multiple transporters [organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, OATP1A2, OATP2B1, sodium-taurocholate cotransporting polypeptide, breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), MRP4, organic anion transporter 3]. It is therefore frequently used as a probe substrate in clinical drug-drug interaction (DDI) studies to investigate transporter inhibition. Although each of these transporters is believed to play a role in rosuvastatin disposition, multiple pharmacogenetic studies confirm that OATP1B1 and BCRP play an important role in vivo. Ronacaleret, a drug-development candidate for treatment of osteoporosis (now terminated), was shown to inhibit OATP1B1 in vitro (IC = 11 µM), whereas it did not inhibit BCRP. Since a DDI risk through inhibition of OATP1B1 could not be discharged, a clinical DDI study was performed with rosuvastatin before initiation of phase II trials. Unexpectedly, coadministration with ronacaleret decreased rosuvastatin exposure by approximately 50%, whereas time of maximal plasma concentration and terminal half-life remained unchanged, suggesting decreased absorption and/or enhanced first-pass elimination of rosuvastatin. Of the potential in vivo rosuvastatin transporter pathways, two might explain the observed results: intestinal OATP2B1 and hepatic MRP4. Further investigations revealed that ronacaleret inhibited OATP2B1 (in vitro IC = 12 µM), indicating a DDI risk through inhibition of absorption. Ronacaleret did not inhibit MRP4, discharging the possibility of enhanced first-pass elimination of rosuvastatin (reduced basolateral secretion from hepatocytes into blood). Therefore, a likely mechanism of the observed DDI is inhibition of intestinal OATP2B1, demonstrating the in vivo importance of this transporter in rosuvastatin absorption in humans.
“…Following removal of preincubation solution, 400 ml of HBSS supplemented with 10 mM HEPES (OATP1B1 only) or DPBS containing ronacaleret at the previously listed target concentrations and 1 mM (OATP1B1, OATP1B3, and OATP2B1) or 5 mM (OATP1A2) rosuvastatin was added to the wells in triplicate. Rosuvastatin substrate concentrations for these transporters in the present study were lower than the published K m values (van de Steeg et al, 2013;Bosgra et al, 2014;Lu et al, 2015). Cells were incubated at 37°C for 3 minutes for OATP1B1, OATP1B3, and OATP1A2 and for 10 minutes for OATP2B1.…”
Rosuvastatin is a widely prescribed antihyperlipidemic which undergoes limited metabolism, but is an in vitro substrate of multiple transporters [organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, OATP1A2, OATP2B1, sodium-taurocholate cotransporting polypeptide, breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), MRP4, organic anion transporter 3]. It is therefore frequently used as a probe substrate in clinical drug-drug interaction (DDI) studies to investigate transporter inhibition. Although each of these transporters is believed to play a role in rosuvastatin disposition, multiple pharmacogenetic studies confirm that OATP1B1 and BCRP play an important role in vivo. Ronacaleret, a drug-development candidate for treatment of osteoporosis (now terminated), was shown to inhibit OATP1B1 in vitro (IC = 11 µM), whereas it did not inhibit BCRP. Since a DDI risk through inhibition of OATP1B1 could not be discharged, a clinical DDI study was performed with rosuvastatin before initiation of phase II trials. Unexpectedly, coadministration with ronacaleret decreased rosuvastatin exposure by approximately 50%, whereas time of maximal plasma concentration and terminal half-life remained unchanged, suggesting decreased absorption and/or enhanced first-pass elimination of rosuvastatin. Of the potential in vivo rosuvastatin transporter pathways, two might explain the observed results: intestinal OATP2B1 and hepatic MRP4. Further investigations revealed that ronacaleret inhibited OATP2B1 (in vitro IC = 12 µM), indicating a DDI risk through inhibition of absorption. Ronacaleret did not inhibit MRP4, discharging the possibility of enhanced first-pass elimination of rosuvastatin (reduced basolateral secretion from hepatocytes into blood). Therefore, a likely mechanism of the observed DDI is inhibition of intestinal OATP2B1, demonstrating the in vivo importance of this transporter in rosuvastatin absorption in humans.
“…The authors postulated an effect on T4 elimination from enterocytes, and not on T4 absorption, that may impair the hormonal enterohepatic recycling and thus bioavailability (35). The evidence that β-blockers and tricyclic antidepressants may use this same transporter shed light on a novel site of interaction with thyroxine (76). A similar involvement in the process of recycling of thyroid hormones from ileum to the liver has been proposed also for OATP4A1, through the portal vein (77).…”
Section: Transport Of Thyroxine Across the Intestinal Mucosamentioning
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“…For example, orange juice and apple juice have been shown to reduce significantly the systemic exposure to fexofenadine, some beta‐blockers, and aliskiren by at least 50% . More recently, constituents in a green tea beverage were reported to decrease systemic exposure to the beta‐blocker, nadolol, by 85% in healthy volunteers by inhibiting intestinal OATP1A2, albeit the existence of this transporter is controversial ; this reduction in systemic exposure was accompanied by an attenuated reduction in systolic blood pressure . These observations prompted evaluation of a streamlined approach for pre‐clinical testing of candidate intestinal OATP inhibitors using grapefruit juice as an archetypal, well‐characterized natural product with successful in vitro – in vivo extrapolated drug interaction liability.…”
Natural products, including botanical dietary supplements and exotic drinks, represent an ever-increasing share of the health care market. The parallel ever-increasing popularity of self-medicating with natural products increases the likelihood of co-consumption with conventional drugs, raising concerns for unwanted natural product-drug interactions. Assessing the drug interaction liability of natural products is challenging due to the complex and variable chemical composition inherent to these products, necessitating a streamlined preclinical testing approach to prioritize precipitant individual constituents for further investigation. Such an approach was evaluated in the current work to prioritize constituents in the model natural product, grapefruit juice, as inhibitors of intestinal organic anion-transporting peptide (OATP)-mediated uptake. Using OATP2B1-expressing MDCKII cells and the probe substrate estrone 3-sulfate, IC50s were determined for constituents representative of the flavanone (naringin, naringenin, hesperidin), furanocoumarin (bergamottin, 6′,7′-dihydroxybergamottin), and polymethoxyflavone (nobiletin and tangeretin) classes contained in grapefruit juice juice. Nobiletin was the most potent (IC50, 3.7 μM); 6′,7′-dihydroxybergamottin, naringin, naringenin, and tangeretin were moderately potent (IC50, 20–50 μM); and bergamottin and hesperidin were the least potent (IC50, >300 μM) OATP2B1 inhibitors. Intestinal absorption simulations based on physiochemical properties were used to determine ratios of unbound concentration to IC50 for each constituent within enterocytes and to prioritize in order of pre-defined cut-off values. This streamlined approach could be applied to other natural products that contain multiple precipitants of natural product-drug interactions.
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