The Effects of Genetic Polymorphisms in the Organic Cation Transporters OCT1, OCT2, and OCT3 on the Renal Clearance of Metformin

Tzvetkov, Mladen V.; Vormfelde, V. Stefan; Balen, Daniela; Meineke, Ingolf; Schmidt, Tobias; Sehrt, Daniel; Sabolić, Ivan; Koepsell, Hermann; Brockmöller, Jürgen

doi:10.1038/clpt.2009.92

Cited by 291 publications

(269 citation statements)

References 47 publications

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“…The role of single nucleotide polymorphisms (SNPs) in the interindividual response to metformin is not yet fully elucidated, but several studies suggest that polymorphisms in OCT1 alter the response to metformin treatment [25][26][27]. The current research regarding the SNP rs316019 (808 G>T) in the gene encoding OCT2 is conflicting, but it does appear to affect the renal clearance (CLR) of metformin [28,29].…”

Section: Study Participantsmentioning

confidence: 99%

Intake ofStJohn's wort improves the glucose tolerance in healthy subjects who ingest metformin compared with metformin alone

Stage

Pedersen

Damkier

et al. 2015

Brit J Clinical Pharma

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AIMSOur objective was to investigate the steady-state pharmacokinetic and pharmacodynamic interaction between the antidepressive herbal medicine St John's wort and the antidiabetic drug metformin. METHODSWe performed an open cross-over study in 20 healthy male subjects, who received 1 g of metformin twice daily for 1 week with and without 21 days of preceding and concomitant treatment with St John's wort. The pharmacokinetics of metformin was determined, and a 2 h oral glucose tolerance test was performed. RESULTSSt John's wort decreased the renal clearance of metformin but did not affect any other metformin pharmacokinetic parameter. The addition of St John's wort decreased the area under the glucose concentration-time curve [702 (95% confidence interval, 643-761) vs. 629 min*mmol/L (95% confidence interval, 568-690), P = 0.003], and this effect was caused by a statistically significant increase in the acute insulin response. CONCLUSIONSSt John's wort improves glucose tolerance by enhancing insulin secretion independently of insulin sensitivity in healthy male subjects taking metformin. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT?• The pregnane X receptor agonist rifampicin lowers the plasma concentration of metformin and increases the glucose tolerance in healthy individuals.• It has not previously been investigated whether the herbal medicine St John's wort (SJW), which is also an agonist of the pregnane X receptor, exerts the same effect. WHAT THIS STUDY ADDS• There was no difference in the pharmacokinetics of metformin, except for a small albeit statistically significant reduction in renal clearance after treatment with SJW.• We show that SJW increases glucose tolerance in healthy subjects who ingest metformin.• The effect was caused by an increase in the acute insulin response.

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Section: Study Participantsmentioning

confidence: 99%

Intake ofStJohn's wort improves the glucose tolerance in healthy subjects who ingest metformin compared with metformin alone

Stage

Pedersen

Damkier

et al. 2015

Brit J Clinical Pharma

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“…11,29 On the other hand, low-function SLC22A1 variants including R61C, G401S and G465R have been associated with significantly higher rates of renal clearance of metformin. 30 In addition to the effect on metformin pharmacokinetics, low-function SLC22A1 variants have been also associated with significantly decreased glucose-lowering response of metformin. 2 For the SLC22A6 gene, one haplotype block ranging from rs4149170 to rs4149172 was obtained in Asian populations, and none was defined in African-American and European-American cohorts (Figures 1 and 2d).…”

Section: Resultsmentioning

confidence: 99%

Screening of genetic variations of SLC15A2, SLC22A1, SLC22A2 and SLC22A6 genes

Cheong

Kim

et al. 2011

J Hum Genet

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A growing list of membrane-spanning proteins involved in the transport of a large variety of drugs has been recognized and characterized to include peptide and organic anion/cation transporters. Given such an important role of transporter genes in drug disposition process, the role of single-nucleotide polymorphisms (SNPs) in such transporters as potential determinants of interindividual variability in drug disposition and pharmacological response has been investigated. To define the distribution of transporter gene SNPs across ethnic groups, we screened 450 DNAs in cohorts of 250 Korean, 50 Han Chinese, 50 Japanese, 50 African-American and 50 European-American ancestries for 64 SNPs in four transporter genes encoding proteins of the solute carrier family (SLC15A2, SLC22A1, SLC22A2 and SLC22A6). Of the 64 SNPs, 19 were core pharmacogenetic variants and 45 were HapMap tagging SNPs. Polymorphisms were genotyped using the golden gate genotyping assay. After genetic variability, haplotype structures and ethnic diversity were analyzed, we observed that the distributions of SNPs in a Korean population were similar to other Asian groups (Chinese and Japanese), and significantly different from African-American and European-American cohorts. Findings from this study would be valuable for further researches, including pharmacogenetic studies for drug responses.

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“…However, there is no report on contribution of different SNPs of OCT1 on clinical outcomes/adverse effects of morphine. Four loss of function OCT1 variants have been reported before: Arg61Cys (rs12208357), Cys88Arg (rs55918055), Gly401Ser (rs34130495) and Gly465Arg (rs34059508), and change of Met420 (rs72552763) amino acids [20,21]. Tzvetkov et al [19] showed in vitro studies that morphine uptake was increased up to fourfold in HEK293 cells overexpressing human OCT1.…”

Section: Discussionmentioning

confidence: 99%

OCT1 Genetic Variants are Associated with Postoperative Morphine-Related Adverse Effects in Children

et al. 2017

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Aim: Large interindividual variability in morphine pharmacokinetics (PK) could contribute to variability in morphine analgesia and adverse events. Respiratory depression (RD) and postoperative nausea and vomiting (PONV) are significant adverse drug response of intravenous morphine in the perioperative setting limiting its efficacy in achieving adequate surgical pain relief. OCT1 is a transporter in the liver that transports morphine from the bloodstream into hepatocytes. Earlier we reported association of genetic polymorphisms in OCT1 with morphine PK, and lower morphine clearance in Caucasian children as compared with African–American (AA) children. The aim of this study is to identify the association between common OCT1 genotypes affecting morphine’s PK and clinically important postoperative morphine-related adverse outcomes. Methods: After obtaining institutional review board (IRB) approval and informed consents, 311 children ages 6–15 years, American Society of Anesthesiologists’ physical status 1 or 2 scheduled for tonsillectomy who received standard anesthetic, surgical and postoperative care were recruited. Clinical data collected included postoperative pain scores, total opioid use, incidence of PONV and RD. Four nonsynonymous SNPs of the OCT1 gene (rs12208357, rs34130495, rs72552763 and rs34059508) in each patient were genotyped using commercially available TaqMan assays. We investigated the genetic association of OCT1 with incidences of postoperative RD and PONV. Results: Caucasian and AA children differed significantly in the incidence of obstructive sleep apnea (p < 0.001) and total morphine use (p = 0.028). There were incidences of prolonged post anesthesia care unit stay in 7% of Caucasian children, while no such incidences were observed for AA children (p = 0.05). OCT1 polymorphism rs12208357 was associated with high incidences of PONV and PONV leading to prolonged post anesthesia care unit stay (p < 0.05). A significant association was also found between rs72552763 GAT deletion and high incidence of RD (p = 0.007). Conclusion: Children with certain OCT1 genotypes are associated with higher risk for RD and PONV following morphine administration leading to prolonged hospital stay. The OCT1 transporters’ effects on morphine’s PK could explain this association.

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The Effects of Genetic Polymorphisms in the Organic Cation Transporters OCT1, OCT2, and OCT3 on the Renal Clearance of Metformin

Cited by 291 publications

References 47 publications

Intake ofStJohn's wort improves the glucose tolerance in healthy subjects who ingest metformin compared with metformin alone

Intake ofStJohn's wort improves the glucose tolerance in healthy subjects who ingest metformin compared with metformin alone

Screening of genetic variations of SLC15A2, SLC22A1, SLC22A2 and SLC22A6 genes

OCT1 Genetic Variants are Associated with Postoperative Morphine-Related Adverse Effects in Children

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