Influence of the organic anion-transporting polypeptide 1B1 (OATP1B1) polymorphisms on irinotecan-pharmacokinetics and clinical outcome of patients with advanced non-small cell lung cancer

Han, Ji‐Youn; Lim, Hyeong‐Seok; Shin, Eak Kyun; Yoo, Young Je; Park, Yong Hoon; Lee, Jong-Eun; Kim, Heung Tae; Lee, Jin Soo

doi:10.1016/j.lungcan.2007.07.019

Cited by 86 publications

(55 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In fact, SLCO1B1*15, which causes reduced transport activity (23), is reported to influence the area under the plasma concentration-time curve of SN-38 and irinotecan-induced toxicity (24,25). Further studies are warranted to examine the effects of genetic polymorphisms in SLCO1B1 on the pharmacokinetics of as well as toxicity of irinotecan.…”

Section: Discussionmentioning

confidence: 99%

Direct Inhibition and Down-regulation by Uremic Plasma Components of Hepatic Uptake Transporter for SN-38, an Active Metabolite of Irinotecan, in Humans

et al. 2013

View full text Add to dashboard Cite

2 ABSTRACTPurpose: Clinical study has previously revealed that plasma concentration of , an active metabolite of irinotecan, was higher in patients with end-stage renal failure than those with normal kidney function although SN-38 is mainly eliminated in the liver. Here, we focused on inhibition by uremic toxins of hepatic SN-38 uptake and down-regulation of uptake transporter(s) by uremic plasma in humans. Methods:We evaluated SN-38 uptake and its inhibition by uremic toxins, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), indoxyl sulfate (Indox), hippuric acid (HA) and indole acetate (IA), with cryopreserved human hepatocytes and HEK293 cells stably expressing hepatic uptake transporters, organic anion transporting polypeptides (OATPs). We also collected plasma samples from patients with severe renal failure to examine their effects on mRNA level of OATPs in primary cultured human hepatocytes.Results: SN-38 was taken up by hepatocytes, which showed biphasic saturation patterns. The SN-38 uptake by hepatocytes was significantly inhibited by a uremic toxin mixture including clinically relevant concentrations of CMPF, Indox, HA and IA. 3Kinetic analyses for OATP-mediated transport revealed that the uptake of SN-38 by OATP1B1 was the highest, followed by OATP1B3. Among the uremic toxins, CMPF exhibited most potent inhibition of OATP1B1-mediated SN-38 uptake and directly inhibited the uptake of SN-38 also in hepatocytes. In addition, gene expression of OATP1B1 and OATP1B3 in hepatocytes was significantly down-regulated by the treatment with the uremic plasma.Conclusions: OATP1B1-mediated hepatic uptake of SN-38 was inhibited by uremic toxins, and gene expression of OATP1B1 was down-regulated by uremic plasma.

show abstract

Section: Discussionmentioning

confidence: 99%

Direct Inhibition and Down-regulation by Uremic Plasma Components of Hepatic Uptake Transporter for SN-38, an Active Metabolite of Irinotecan, in Humans

et al. 2013

View full text Add to dashboard Cite

show abstract

“…A previous report indicated that SN-38 is a substrate of OATP1B1 and its transport was significantly lower in OATP1B1*15-expressing cells compared with OATP1B1*1a-expressing cells. 58) In cancer patients treated with irinotecan, the plasma concentration of SN-38 was higher and the risk of severe neutropenia was increased by c.521T>C, while the risk of severe diarrhea (intestinal toxicity) was increased by c.388A>G. 59) This was explained by the increased exposure of SN-38 to the precursor of blood cells by c.521T>C and its increased exposure to the intestinal tract due to the increased biliary excretion of SN-38 by c.388A>G. In the case of methotrexate, an intronic mutation in SLCO1B1, rs11045879C>T, increased the clearance of methotrexate and increased the risk of severe intestinal toxicity 16.4-fold, while c.521T>C decreased the methotrexate clearance and the risk of intestinal toxicity. 60) Shitara et al tried to simultaneously estimate the contribution of OATP1B1 to the overall hepatic uptake of OATP substrate drugs and decreased function of OATP1B1 by c.521T>C mutation in humans based on previous clinical pharmacogenetic studies.…”

Section: Genetic Polymorphisms Of Oatp1b1 and Oatp1b3 And Their Clinimentioning

confidence: 99%

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

Maeda

2015

Biological & Pharmaceutical Bulletin

119

View full text Add to dashboard Cite

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.

show abstract

“…Di Martino and colleagues reported variants in ABCC5 (rs562), ABCG1 (rs425215), and SLCO1B1 (rs2306283) that were associated with grade 3þ gastrointestinal toxicity in irinotecan-treated patients (37). Interestingly, this SLCO1B1 SNP has been identified in other candidate association studies to be a predictor of irinotecan toxicity risk (38,39). This same group published a case-control analysis of zoledronic acid-induced osteonecrosis of the jaw, which identified SNPs in PPARG, ABP1, CHST11, and CROT (40); however, none of these genes were associated with this phenotype in a large GWAS (41).…”

Section: Panels With Defined Snp Listsmentioning

confidence: 96%

Using Pharmacogene Polymorphism Panels to Detect Germline Pharmacodynamic Markers in Oncology

Hertz¹,

McLeod²

2014

Clinical Cancer Research

View full text Add to dashboard Cite

The patient (germline) genome can influence the pharmacokinetics and pharmacodynamics of cancer therapy. The field of pharmacogenetics (PGx) has primarily focused on genetic predictors of pharmacokinetics, largely ignoring pharmacodynamics, using a candidate approach to assess single-nucleotide polymorphisms (SNP) with known relevance to drug pharmacokinetics such as enzymes and transporters. A more comprehensive approach, the genome-wide association study, circumvents candidate selection but suffers because of the necessity for substantial statistical correction. Pharmacogene panels, which interrogate hundreds to thousands of SNPs in genes with known relevance to drug pharmacokinetics or pharmacodynamics, represent an attractive compromise between these approaches. Panels with defined or customizable SNP lists have been used to discover SNPs that predict pharmacokinetics or pharmacodynamics of cancer drugs, most of which await successful replication. PGx discovery, particularly for SNPs that influence drug pharmacodynamics, is limited by weaknesses in both genetic and phenotypic data. Selection of candidate SNPs for inclusion on pharmacogene panels is difficult because of limited understanding of biology and pharmacology. Phenotypes used in analyses have primarily been complex toxicities that are known to be multifactorial. A more measured approach, in which sensitive phenotypes are used in place of complex clinical outcomes, will improve the success rate of pharmacodynamics SNP discovery and ultimately enable identification of pharmacodynamics SNPs with meaningful effects on treatment outcomes.

show abstract

Influence of the organic anion-transporting polypeptide 1B1 (OATP1B1) polymorphisms on irinotecan-pharmacokinetics and clinical outcome of patients with advanced non-small cell lung cancer

Cited by 86 publications

References 21 publications

Direct Inhibition and Down-regulation by Uremic Plasma Components of Hepatic Uptake Transporter for SN-38, an Active Metabolite of Irinotecan, in Humans

Direct Inhibition and Down-regulation by Uremic Plasma Components of Hepatic Uptake Transporter for SN-38, an Active Metabolite of Irinotecan, in Humans

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

Using Pharmacogene Polymorphism Panels to Detect Germline Pharmacodynamic Markers in Oncology

Contact Info

Product

Resources

About