Intestinal Absorption of HMG-CoA Reductase Inhibitor Pravastatin Mediated by Organic Anion Transporting Polypeptide

Shirasaka, Yoshiyuki; Suzuki, Kensuke; Nakanishi, Takeo; Tamai, Ikumi

doi:10.1007/s11095-010-0216-5

Cited by 70 publications

(54 citation statements)

References 42 publications

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“…Xenopus laevis frogs were purchased from Kato-S-Science (Chiba, Japan). Preparation of oocytes, in vitro synthesis of OATP2B1 cRNA, and uptake experiments were conducted as described previously (Nozawa et al, 2004;Shirasaka et al, 2010). Xenopus oocytes were used for evaluation of SN-38 transport by OATP2B1, and the accumulated SN-38 was quantitated by high-performance liquid chromatography (HPLC).…”

Section: Methodsmentioning

confidence: 99%

Organic Anion Transporting Polypeptide (OATP)2B1 Contributes to Gastrointestinal Toxicity of Anticancer Drug SN-38, Active Metabolite of Irinotecan Hydrochloride

Fujita

Saito

Nakanishi

et al. 2015

Drug Metabolism and Disposition

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Gastrointestinal toxicity, such as late-onset diarrhea, is a significant concern in irinotecan hydrochloride (CPT-11)-containing regimens. Prophylaxis of late-onset diarrhea has been reported with use of Japanese traditional (Kampo) medicine containing baicalin and with the antibiotic cefixime, and this has been explained in terms of inhibition of bacterial deconjugation of SN-38-glucuronide since unconjugated SN-38 (active metabolite of CPT-11) is responsible for the gastrointestinal toxicity. It is also prerequisite for SN-38 to be accumulated in intestinal tissues to exert toxicity. Based on the fact that liver-specific organic anion transporting polypeptide (OATP) 1B1, a member of the same family as OATP2B1, is known to be involved in hepatic transport of SN-38, we hypothesized that intestinal transporter OATP2B1 contributes to the accumulation of SN-38 in gastrointestinal tissues, and its inhibition would help prevent associated toxicity. We found that uptake of SN-38 by OATP2B1-expressing Xenopus oocytes was significantly higher than that by control oocytes. OATP2B1-mediated uptake of SN-38 was saturable, pH dependent, and decreased in the presence of baicalin, cefixime, or fruit juices such as apple juice. In vivo gastrointestinal toxicity of SN-38 in mice caused by oral administration for consecutive 5 days was prevented by coingestion of apple juice. Thus, OATP2B1 contributes to the uptake of SN-38 by intestinal tissues, triggering gastrointestinal toxicity. So, in addition to the reported inhibition of bacterial b-glucuronidase by cefixime or baicalin, inhibition of OATP2B1 may also contribute to prevention of gastrointestinal toxicity. Apple juice may be helpful for prophylaxis of late-onset diarrhea observed in CPT-11 therapy without disturbance of the intestinal microflora.

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Section: Methodsmentioning

confidence: 99%

Organic Anion Transporting Polypeptide (OATP)2B1 Contributes to Gastrointestinal Toxicity of Anticancer Drug SN-38, Active Metabolite of Irinotecan Hydrochloride

Fujita

Saito

Nakanishi

et al. 2015

Drug Metabolism and Disposition

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“…The maximum drug concentration (C max ) of 15.61 ± 4.92 ng/ml was achieved at a T max of 0.350 ± 0.136 h (Tayel et al, 2015). The double-peak phenomenon in the drug plasma concentration-time curves was previously correlated to the rapid drug absorption at its main site of absorption and the delayed drug re-absorption from the enterohepatic circulation into the circulation, respectively (Sun et al, 2009;Shirasaka et al, 2010). Needless to say, PVS is one of the drugs that undergo extensive first pass metabolism where around 50% of dose is metabolized before reaching the systemic circulation (Quion & Jones, 1994).…”

Section: Formulamentioning

confidence: 99%

Duodenum-triggered delivery of pravastatin sodium: II. Design, appraisal and pharmacokinetic assessments of enteric surface-decorated nanocubosomal dispersions

et al. 2016

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Context: Pravastatin sodium (PVS) is a freely water-soluble HMG-CoA inhibitor that suffers from instability at gastric pH, extensive first pass metabolism, short elimination half-life (1-3 h) and low oral bioavailability (18%). Objective: To overpower these drawbacks and to maximize drug absorption at its main site of absorption at the duodenum, enteric surface-coated PVS-loaded nanocubosomal dispersions were presented. Materials and methods: Glyceryl monooleate (GMO)-based dispersions were developed by the fragmentation or the liquid precursor methods using Pluronic Õ F127 or Cremophor Õ EL as surfactants. As a challenging entericcoating approach, the promising dispersions were surface-coated via lyophilization with Eudragit Õ L100-55; a duodenum-targeting polymer. The drug content, particle size, zeta potential, morphology and release studies of PVS-loaded dispersions were evaluated before and after surface-coating. Compared to an aqueous PVS solution, the pharmacokinetics of the best achieved system (E-F8) was evaluated (UPLC-MS/MS) in rats. Results: The enteric surfacecoated nanocubosomal dispersions were more or less spherical in shape and showed high drug-loading, negative zeta potential values and fine-tuned biphasic drug-release patterns characterized by retarded (2 h) and sustained (10 h) phases in pH 1.2 and pH 6.8, respectively. E-F8 system showed significantly (p50.05) higher oral bioavailability, delayed T max and prolonged MRT 0À1 following oral administration in rats. Conclusions: The duodenum-triggering potential and the controlled-release characteristics of the best achieved system for smart PVS delivery were revealed.

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“…Notably, OATP2B1 uptake appears to be pH-sensitive, diminishing greatly as the pH increases from 5.0 to 7.4. [66][67][68] This observation suggests that the primary impact of OATP2B1 translocation occurs at the level of the enterocyte, where it is exposed to lower pH values, as opposed to the hepatocyte, where the systemic pH is higher and less uptake is expected. Pravastatin is not a substrate for the efflux transporters MDR1 and BCRP but, in vitro, appears to be a substrate for the efflux transporter MRP2, which is located on the apical surface of the enterocyte and liver.…”

Section: Absorptionmentioning

confidence: 99%

“…Pravastatin is not a substrate for the efflux transporters MDR1 and BCRP but, in vitro, appears to be a substrate for the efflux transporter MRP2, which is located on the apical surface of the enterocyte and liver. [68][69][70][71] In vivo, increased expression of MRP2 conferred by a 'gain of function' sequence variation (ABCC2 c.1446C>G), increases presystemic clearance and reduces the bioavailability of pravastatin at the level of the enterocyte. 72 Rosuvastatin similarly undergoes transportermediated absorption and, although not fully characterized, also appears be a substrate for OATP2B1 and BCRP.…”

Section: Absorptionmentioning

confidence: 99%

Pediatric Statin Administration: Navigating a Frontier with Limited Data

Wagner

Abdel‐Rahman

2016

The Journal of Pediatric Pharmacology and Therapeutics

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Increasingly, children and adolescents with dyslipidemia qualify for pharmacologic intervention. As they are for adults, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) are the mainstay of pediatric dyslipidemia treatment when lifestyle modifications have failed. Despite the overall success of these drugs, the magnitude of variability in dose-exposure-response profiles contributes to adverse events and treatment failure. In children, the cause of treatment failures remains unclear. This review describes the updated guidelines for screening and management of pediatric dyslipidemia and statin disposition pathway to assist the provider in recognizing scenarios where alterations in dosage may be warranted to meet patients' specific needs.

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Intestinal Absorption of HMG-CoA Reductase Inhibitor Pravastatin Mediated by Organic Anion Transporting Polypeptide

Abstract: Oatp, but not by Mdr1 or Bcrp, contributes to the intestinal absorption of pravastatin in rats.

Cited by 70 publications

References 42 publications

Organic Anion Transporting Polypeptide (OATP)2B1 Contributes to Gastrointestinal Toxicity of Anticancer Drug SN-38, Active Metabolite of Irinotecan Hydrochloride

Organic Anion Transporting Polypeptide (OATP)2B1 Contributes to Gastrointestinal Toxicity of Anticancer Drug SN-38, Active Metabolite of Irinotecan Hydrochloride

Duodenum-triggered delivery of pravastatin sodium: II. Design, appraisal and pharmacokinetic assessments of enteric surface-decorated nanocubosomal dispersions

Pediatric Statin Administration: Navigating a Frontier with Limited Data

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