Influence of SLCO1B1 and CYP2C8gene polymorphisms on rosiglitazone pharmacokinetics in healthy volunteers

Aquilante, Christina L.; Bushman, Lane R.; Knutsen, Shannon D; Burt, Lauren E; Rome, Lucille Capo; Kosmiski, Lisa A.

doi:10.1186/1479-7364-3-1-7

Cited by 46 publications

(29 citation statements)

References 32 publications

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“…The SLCO1B1 polymorphisms, g.-11187G>A (rs4149015), c.388A>G (rs2306283), and c.521T>C (rs4149056), were genotyped in duplicate using PCR-pyrosequencing analysis (PSQ 96 MA, Qiagen) according to a previously published method. 43 Genotype determinations were made using automated PSQ 96MA SNP software, version 2.0 (Qiagen). SLCO1B1 haplotypes were computationally assigned using HelixTree Genetics Analysis Software (Golden Helix, Inc, Bozeman, Montana) as follows: *1A (-11187G/388A/521T), *1B (-11187G/388G/521T), *5 (-11187G/388A/521C), *15 (-11187G/388G/521C), and *17 (-11187A/388G/521C).…”

Section: Genetic Analysesmentioning

confidence: 99%

Influence of SLCO1B1 Polymorphisms on the Drug‐Drug Interaction Between Darunavir/Ritonavir and Pravastatin

Aquilante

Kiser

Anderson

et al. 2012

The Journal of Clinical Pharma

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The authors investigated whether SLCO1B1 polymorphisms contribute to variability in pravastatin pharmacokinetics when pravastatin is administered alone versus with darunavir/ritonavir. HIV-negative healthy participants were prospectively enrolled on the basis of SLCO1B1 diplotype: group 1 (*1A/*1A, n = 9); group 2 (*1A/*1B, n = 10; or *1B/*1B, n = 2); and group 3 (*1A/*15, n = 1; *1B/*15, n = 5; or *1B/*17, n = 1). Participants received pravastatin (40 mg) daily on days 1 through 4, washout on days 5 through 11, darunavir/ritonavir (600/100 mg) twice daily on days 12 through 18, with pravastatin 40 mg added back on days 15 through 18. Pharmacokinetic studies were conducted on day 4 (pravastatin alone) and day 18 (pravastatin + darunavir/ritonavir). Pravastatin area under the plasma concentration-time curve (AUC(tau)) was 21% higher during administration with darunavir/ritonavir compared with pravastatin alone; however, this difference was not statistically significant (P = .11). Group 3 variants had 96% higher pravastatin AUC(tau) on day 4 and 113% higher pravastatin AUC(tau) on day 18 compared with group 1. The relative change in pravastatin pharmacokinetics was largest in group 3 but did not differ significantly between diplotype groups. In sum, the influence of SLCO1B1*15 and *17 haplotypes on pravastatin pharmacokinetics was maintained in the presence of darunavir/ritonavir. Because OATP1B1 inhibition would be expected to be greater in carriers of normal or high-functioning SLCO1B1 haplotypes, these findings suggest that darunavir/ritonavir is not a potent inhibitor of OATP1B1-mediated pravastatin transport in vivo.

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Section: Genetic Analysesmentioning

confidence: 99%

Influence of SLCO1B1 Polymorphisms on the Drug‐Drug Interaction Between Darunavir/Ritonavir and Pravastatin

Aquilante

Kiser

Anderson

et al. 2012

The Journal of Clinical Pharma

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“…71 Genetic variation in CYP2C8 was reported to influence the PK of rosiglitazone with significantly lower AUC and higher oral clearance for *1/*3 subjects compared with *1/*1 subjects. 71 Although it was hypothesized that the lower metabolic activity CYP2C8*2 and *3 variants would result in decreased metabolism and increased drug levels, clinical studies did not corroborate these assumptions. Instead, they showed higher clearance and lower AUC for subjects with two copies of the *3 alleles compared with the wild type.…”

Section: Thiazolidinediones: Pharmacokinetics/pharmacodynamics and Evmentioning

confidence: 99%

“…Furthermore, TZDs are substrates of OATP1B (SLCO1B1), the main organic anion transporter protein responsible for their active shuttling into hepatocytes. 71 A joint investigation on the effects of CYP2C8 and SLCO1B1 polymorphisms was recently conducted in 833 Scottish patients with T2DM treated with TZDs. 51 Results showed that although the CYP2C8*3 variant was associated with reduced glycemic response to rosiglitazone, the common SCLO1B1 521T>C variant, in contrast, was associated with an enhanced glycemic response.…”

Section: Thiazolidinediones: Pharmacokinetics/pharmacodynamics and Evmentioning

confidence: 99%

Using Personalized Medicine in the Management of Diabetes Mellitus

Elk

Iwuchukwu

2017

Pharmacotherapy

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Diabetes mellitus is a worldwide problem with an immense pharmacoeconomic burden. The multifactorial and complex nature of the disease lends itself to personalized pharmacotherapeutic approaches to treatment. Variability in individual risk and subsequent development of diabetes has been reported in addition to differences in response to the many oral glucose lowering therapies currently available for diabetes pharmacotherapy. Pharmacogenomic studies have attempted to uncover the heritable components of individual variability in risk susceptibility and response to pharmacotherapy. We review the current pharmacogenomics evidence as it relates to common oral glucose lowering therapies and how they can be utilized in the management of polygenic and monogenic forms of diabetes. Evidence supports the use of genetic testing and personalized approaches to the treatment of monogenic diabetes of the young. The data are not as robust for the current application of pharmacogenetic approaches to the treatment of polygenic type 2 diabetes mellitus, but there are suggestions as to future applications in this regard. We reviewed pertinent primary literature sources as well as current evidence-based guidelines on diabetes management.

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“…CYP2C8*2 carriers reported abdominal pain more frequently than wild-type homozygotes in a small study of West African malaria patients taking amodiaquine, suggesting possible clinical relevance for the polymorphism (Parikh et al 2007). The CYP2C8*3 genotype is likewise of considerable interest and has been examined extensively with regard to NSAIDS, antidiabetic agents, and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (Kirchheiner et al 2003;Martinez et al 2005;Kirchheiner et al 2006;Lopez-Rodriguez et al 2008;Aquilante et al 2008;Garcia-Martin et al 2004). In clinical studies, CYP2C8*3 is associated with increased drug metabolism for several substrates as evidenced by significantly decreased plasma concentrations of rosiglitazone, pioglitazone, and repaglinide (Niemi et al 2003(Niemi et al , 2005Kirchheiner et al 2006;Aquilante et al 2008;Tornio et al 2008).…”

mentioning

confidence: 99%

“…The CYP2C8*3 genotype is likewise of considerable interest and has been examined extensively with regard to NSAIDS, antidiabetic agents, and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (Kirchheiner et al 2003;Martinez et al 2005;Kirchheiner et al 2006;Lopez-Rodriguez et al 2008;Aquilante et al 2008;Garcia-Martin et al 2004). In clinical studies, CYP2C8*3 is associated with increased drug metabolism for several substrates as evidenced by significantly decreased plasma concentrations of rosiglitazone, pioglitazone, and repaglinide (Niemi et al 2003(Niemi et al , 2005Kirchheiner et al 2006;Aquilante et al 2008;Tornio et al 2008). In contrast, decreased ibuprofen metabolism has also been noted, implying that the kinetic properties of CYP2C8*3 may be substrate-dependent (Garcia-Martin et al 2004;Martinez et al 2005).…”

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confidence: 99%

In vitro metabolism of exemestane by hepatic cytochrome P450s: impact of nonsynonymous polymorphisms on formation of the active metabolite 17β‐dihydroexemestane

Peterson

Xia

Chen

et al. 2017

Pharmacology Res & Perspec

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Exemestane (EXE) is an endocrine therapy commonly used by postmenopausal women with hormone‐responsive breast cancer due to its potency in inhibiting aromatase‐catalyzed estrogen synthesis. Preliminary in vitro studies sought to identify phase I EXE metabolites and hepatic cytochrome P450s (CYP450s) that participate in EXE biotransformation. Phase I metabolites were identified by incubating EXE with HEK293‐overexpressed CYP450s. CYP450s 1A2, 2C8, 2C9, 2C19, 2D6, 3A4, and 3A5 produce 17β‐dihydroexemestane (17β‐DHE), an active major metabolite, as well as two inactive metabolites. 17β‐DHE formation in pooled human liver microsomes subjected to isoform‐specific CYP450 inhibition was also monitored using tandem mass spectrometry. 17β‐DHE production in human liver microsomes was unaffected by isoform‐specific inhibition of CYP450s 2A6, 2B6, and 2E1 but decreased 12–39% following inhibition of drug‐metabolizing enzymes from CYP450 subfamilies 1A, 2C, 2D, and 3A. These results suggest that redundancy exists in the EXE metabolic pathway with multiple hepatic CYP450s catalyzing 17β‐DHE formation in vitro. To further expand the knowledge of phase I EXE metabolism, the impact of CYP450 genetic variation on 17β‐DHE formation was assessed via enzyme kinetic parameters. Affinity for EXE substrate and enzyme catalytic velocity were calculated for hepatic wild‐type CYP450s and their common nonsynonymous variants by monitoring the reduction of EXE to 17β‐DHE. Several functional polymorphisms in xenobiotic‐metabolizing CYP450s 1A2, 2C8, 2C9, and 2D6 resulted in deviant enzymatic activity relative to wild‐type enzyme. Thus, it is possible that functional polymorphisms in EXE‐metabolizing CYP450s contribute to inter‐individual variability in patient outcomes by mediating overall exposure to the drug and its active metabolite, 17β‐DHE.

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Influence of SLCO1B1 and CYP2C8gene polymorphisms on rosiglitazone pharmacokinetics in healthy volunteers

Cited by 46 publications

References 32 publications

Influence of SLCO1B1 Polymorphisms on the Drug‐Drug Interaction Between Darunavir/Ritonavir and Pravastatin

Influence of SLCO1B1 Polymorphisms on the Drug‐Drug Interaction Between Darunavir/Ritonavir and Pravastatin

Using Personalized Medicine in the Management of Diabetes Mellitus

In vitro metabolism of exemestane by hepatic cytochrome P450s: impact of nonsynonymous polymorphisms on formation of the active metabolite 17β‐dihydroexemestane

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