Effects of Acid and Lactone Forms of Eight HMG-CoA Reductase Inhibitors on CYP-Mediated Metabolism and MDR1-Mediated Transport

Sakaeda, Toshiyuki; Fujino, Hideki; Komoto, Chiho; Kakumoto, Mikio; Jin, Jiang-shu; Iwaki, Kentaro; Nishiguchi, Kohshi; Nakamura, Tsutomu; Okamura, Noboru; Okumura, Katsuhiko

doi:10.1007/s11095-005-9371-5

Cited by 84 publications

(66 citation statements)

References 49 publications

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“…Based on available data, pravastatin is unlikely to be a substrate of CYP3A4 or CYP2C9; the co-administration of CYP3A4 inhibitors (i.e., verapamil, mibefradil, itraconazole, clarithromycin, and grapefruit juice) or CYP2C9 inhibitor (i.e., fluconazole) had no significant effect on the pharmacokinetics of pravastatin (Fukazawa et al 2003;Jacobson 2004;Kantola et al 2000). Additionally, in vitro inhibition profiles of major human drug metabolizing CYP isoenzymes (i.e., CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP3A5) by pravastatin showed that both acid and lactone forms of pravastatin had minimal inhibitory effects on metabolic activities of all five CYP isoenzymes with IC 50 values [100 lM (Sakaeda et al 2006). Taking these into consideration, increased AUC and decreased CL t /F of olmesartan in the co-administration phase are unlikely to result from the inhibition of CYP-mediated metabolism of olmesartan by pravastatin.…”

Section: Resultsmentioning

confidence: 98%

Pharmacokinetic interaction between pravastatin and olmesartan in relation to SLCO1B1 polymorphism

et al. 2008

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The impact of SLCO1B1 polymorphism on the pharmacokinetics of olmesartan and on the pharmacokinetic interaction between pravastatin and olmesartan was investigated. On day 1, ten healthy volunteers took an oral dose (10 mg) of pravastatin. After a 3-day washout period, each subject received olmesartan medoxomil (10 mg) for 3 days. On day 8, they received olmesartan medoxomil (10 mg) and pravastatin (10 mg) concurrently, and pharmacokinetic profiles were compared with those in each single-dose phase with regard to the SLCO1B1 genotypes (*1b/*1b, *1b/*15, and *15/*15). In the single-dose phase, the mean C max and AUC 0-24 of olmesartan tended to be higher in *15/*15 subjects than in *1b/*1b subjects, while the mean CL t /F (±SD) in *15/*15 subjects was significantly lower than that in *1b/*1b subjects. No statistically significant differences were observed in any pharmacokinetic parameters between single-dose and co-administration phases for both pravastatin and RMS-416. These results suggest that OATP1B1 plays a role in the pharmacokinetics of olmesartan, and the co-administration of olmesartan does not affect the pharmacokinetics of pravastatin or its metabolite, RMS-416, although larger scale clinical studies are needed to confirm these observations due to the small sample size in the present study.

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Section: Resultsmentioning

confidence: 98%

Pharmacokinetic interaction between pravastatin and olmesartan in relation to SLCO1B1 polymorphism

et al. 2008

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“…This suggests that rosuvastatin may be modified by the CYP3A5 enzyme and that the metabolite either has increased ability to inhibit HMG-CoA reductase or is of a similar inhibitory activity but less readily excreted from the hepatocyte. It has previously been reported that unlike the acid form of rosuvastatin, the lactone form is a good substrate of the CYP3A4/3A5 enzymes, 37,38 and that itraconazole, an inhibitor of CYP3A4, leads to modest increases in rosuvastatin plasma concentrations. 39 Furthermore, atorvastatin, a closely related molecule, has previously been reported to undergo modification by the CYP3A4/3A5 enzymes and yet still retain HMG-CoA reductase inhibitory activity.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial Infarction

Bailey

Romaine

Jackson

et al. 2010

Circ Cardiovasc Genet

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on behalf of the SPACE ROCKET Trial GroupBackground-Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy. Methods and Results-The Genetic Effects On STATins (GEOSTAT-1) Study was a genetic substudy of Secondary Prevention of Acute Coronary Events-Reduction of Cholesterol to Key European Targets (SPACE ROCKET) (a randomized, controlled trial comparing 40 mg of simvastatin and 10 mg of rosuvastatin) that recruited 601 patients after myocardial infarction. We genotyped the following functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes, CYP2C9*2 (430CϾT), CYP2C9*3 (1075AϾC), CYP2C19*2 (681GϾA), CYP3A5*1 (6986AϾG), and hepatic influx and efflux transporters SLCO1B1 (521TϾC) and breast cancer resistance protein (BCRP; 421CϾA). We assessed 3-month LDL cholesterol levels and the proportion of patients reaching the current LDL cholesterol target of Ͻ70 mg/dL (Ͻ1.81 mmol/L). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 (Pϭ0.006) or BCRP (Pϭ0.010). Furthermore, multivariate logistic-regression analysis revealed that patients with at least 1 variant CYP3A5 and/or BCRP allele (nϭ186) were more likely to achieve the LDL cholesterol target (odds ratio: 2.289; 95% CI: 1.157, 4.527; Pϭ0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). There were no differences for patients with variants of CYP2C9, CYP2C19, or SLCO1B1 in comparison with their respective wild types, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (nϭ415; odds ratio: 1.207; 95% CI: 0.768, 1.899; Pϭ0.415). Conclusion-The

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“…12 Unlike other statins, pitavastatin does not undergo extensive metabolism by cytochrome P450 isoenzymes, and hence the potential for interactions with drugs that are metabolized by cytochrome P450 is low. 12,13 A 12-week, randomized, double-blind trial in patients at high risk of CHD showed that pitavastatin 4 mg was statistically non-inferior to simvastatin 40 mg for the reduction of LDL-C concentrations, and provided larger increases in HDL-C (6.8% vs. 4.5%; P=0.083) and reductions in triglycerides (-19.8% vs. -14.8%; P=0.044) than simvastatin treatment. 14 …”

Section: Introductionmentioning

confidence: 99%

Long-term efficacy of pitavastatin versus simvastatin

Eriksson

Budinski²,

Hounslow³

2011

Adv Therapy

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Effects of Acid and Lactone Forms of Eight HMG-CoA Reductase Inhibitors on CYP-Mediated Metabolism and MDR1-Mediated Transport

Cited by 84 publications

References 49 publications

Pharmacokinetic interaction between pravastatin and olmesartan in relation to SLCO1B1 polymorphism

Pharmacokinetic interaction between pravastatin and olmesartan in relation to SLCO1B1 polymorphism

Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial Infarction

Long-term efficacy of pitavastatin versus simvastatin

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