Pharmacogenetics of SLCO1B1 gene and the impact of *1b and *15 haplotypes on irinotecan disposition in Asian cancer patients

Xiang, Xiaoqiang; Jada, Srinivasa Rao; Li, Hui Hua; Fan, Lu; Tham, Lai San; Wong, Chiung Ing; Lee, Soo‐Chin; Lim, Robert; Zhou, Qing Yu; Goh, Boon Cher; Tan, Eng Huat; Chowbay, Balram

doi:10.1097/01.fpc.0000230420.05221.71

Cited by 90 publications

(59 citation statements)

References 36 publications

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“…The clinical relevance of these findings was subsequently validated by comparing the pharmacokinetics and toxicity profiles in patients receiving irinotecan therapy (42,43). Patients with the OATP1B1*15 genotype showed increased systemic exposure and toxicities of SN-38 compared to those with the wild-type OATP1B1 (42,43). Similar findings have been reported with patients treated with methotrexate.…”

Section: Impact Of Oatp Polymorphisms On the Phar Macokinetics Of Antsupporting

confidence: 66%

“…Compared to the wild-type OATP1B1 (OATP1B1*1a), the OATP1B1*15 displayed reduced uptake of SN-38 (an active metabolite of irinotecan), when tested in in vitro cell line models stably expressing OATP1B1 variant proteins (25). The clinical relevance of these findings was subsequently validated by comparing the pharmacokinetics and toxicity profiles in patients receiving irinotecan therapy (42,43). Patients with the OATP1B1*15 genotype showed increased systemic exposure and toxicities of SN-38 compared to those with the wild-type OATP1B1 (42,43).…”

Section: Impact Of Oatp Polymorphisms On the Phar Macokinetics Of Antmentioning

confidence: 99%

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Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

Thakkar

Lockhart

Lee

2015

AAPS J

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Abstract. The superfamily of organic anion-transporting polypeptides (OATPs, gene symbol SLCO) includes important transporters handling a variety of endogenous and xenobiotic substrates. Currently, 11 human OATPs are known and their substrates include endogenous hormones and their conjugates, anticancer drugs, and imaging agents. The contribution of OATPs to the in vivo disposition of these substrates has been extensively investigated. An accumulating body of evidence also indicates that the expression of some OATPs may be up-or downregulated in several types of cancers, suggesting potential pathogenic roles during the development and progression of cancer. Given that the role of OATPs in handling cancer therapeutics has been already covered by several excellent reviews, this review will focus on the recent progresses on the topic, in particular the role of OATPs in the disposition of anticancer drugs, the impact of OATP genetic variations on the function of OATPs, and the OATPs differentially expressed in cancer and their potential roles in cancer development, progression, and treatment.

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Section: Impact Of Oatp Polymorphisms On the Phar Macokinetics Of Antsupporting

confidence: 66%

Section: Impact Of Oatp Polymorphisms On the Phar Macokinetics Of Antmentioning

confidence: 99%

Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

Thakkar

Lockhart

Lee

2015

AAPS J

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“…For example, some single-nucleotide polymorphisms of the genes encoding OATP, BCRP, and MRP2 have been associated with alterations in the pharmacokinetic profiles of statins (Niemi et al, 2006;Xiang et al, 2006;Hua et al, 2012;Konig et al, 2013). The increased expression of OATP and decreased expression of MRP2 may also alter pharmacokinetic parameters and disposition in patients with diabetes (Jung et al, 2001;Kast et al, 2002;Hasegawa et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

The Hepatobiliary Disposition of Timosaponin B2 Is Highly Dependent on Influx/Efflux Transporters but Not Metabolism

Sheng

Tian

et al. 2014

Drug Metab Dispos

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The purpose of this study was to characterize the hepatobiliary disposition of timosaponin B2 (TB-2), a natural saponin. Although TB-2 has multiple pharmacologic activities, the mechanism of its hepatobiliary disposition has not been explored. Because the metabolism of TB-2 is limited and the accumulation of TB-2 in primary hepatocytes is highly temperature dependent (93% of its accumulation is due to active uptake), the contribution of hepatic transporters was investigated. Organic anion-transporting polypeptide (OATP) 1B1-and OATP1B3-transfected human embryonic kidney 293 cells were employed. TB-2 serves as a substrate for OATP1B1 and OATP1B3, with the former playing a predominant role in the hepatic uptake of TB-2. An inhibition study in sandwich-cultured rat hepatocytes suggested that TB-2 is a substrate for both breast cancer resistance protein (Bcrp) and multidrug resistance-associated protein 2 (Mrp2), consistent with its high biliary excretion index (43.1-44.9%). This hypothesis was further verified in BCRP and MRP2 membrane vesicles. The cooperation of uptake and efflux transporters in TB-2 hepatic disposition could partially explain the doublepeak phenomenon observed in rat plasma and liver and biliary clearance, which accounted for 70% of the total TB-2 clearance. Moreover, TB-2 significantly increased the rosuvastatin concentration in rat plasma in a concentration-dependent manner and decreased its biliary excretion, which corresponded to reductions in rosuvastatin accumulation in hepatocytes and the biliary excretion index in sandwich-cultured rat hepatocytes, representing a perfect example of a potential saponin-statin drug-drug interaction. These studies demonstrate that transporters (Oatp, Bcrp/Mrp2), but not metabolism, contribute significantly to rat TB-2 hepatobiliary disposition.

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“…In addition, we showed that SN-38 is a substrate of hepatic uptake transporter organic anion transporting protein (OATP)1B1 (Nozawa et al, 2005). Also, a genetic variant of OATP1B1 with reduced transport activity is associated with increased incidence of life-threatening toxicities resulting from increased systemic exposure to SN-38 (Xiang et al, 2006). Accordingly, both drug transporters and drug-metabolizing enzymes likely contribute to the pharmacologic and toxicologic actions of Another OATP family member, OATP2B1, is expressed in several tissues, including the liver and intestine (Tamai et al, 2000).…”

Section: Introductionmentioning

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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Pharmacogenetics of SLCO1B1 gene and the impact of 1b and 15 haplotypes on irinotecan disposition in Asian cancer patients

Cited by 90 publications

References 36 publications

Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

The Hepatobiliary Disposition of Timosaponin B2 Is Highly Dependent on Influx/Efflux Transporters but Not Metabolism

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

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