Plasma Concentrations Of Lovastatin Research Articles

Effect of Polymorphisms in CYP3A4, PPARA, NR1I2, NFKB1, ABCG2 and SLCO1B1 on the Pharmacokinetics of Lovastatin in Healthy Chinese Volunteers

This study examined whether gene polymorphisms (CYP3A4, ABCG2, SLCO1B1, NR1I2, PPARA and NFKB1) influenced the pharmacokinetics of lovastatin in Chinese healthy subjects. Plasma concentrations of lovastatin and lovastatin acid were quantified using LC/MS/MS. PPARA c.208+3819 G allele carriers had approximately twofold higher AUC0-∞ and Cmax of lovastatin than wild-type (PPARA c.208+3819 AA) subjects. After adjustment for the PPARA variants, subjects with the SLCO1B1 521TT genotype had approximately 50% lower AUC0-∞ of lovastatin acid than those with 521TC/CC genotypes, while the AUC0-∞ of lovastatin lactone in NFKB1-94 DD wild-type carriers was twofold higher than in mutant homozygotes carriers. Gene polymorphisms of PPARA, SLCO1B1 and NFKB1 affected the pharmacokinetics of lovastatin.

SLCO1B1 polymorphism markedly affects the pharmacokinetics of lovastatin acid.

Organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1 gene) is a hepatic uptake transporter, and its genetic variability is associated with pharmacokinetics and muscle toxicity risk of simvastatin. We examined the possible effects of variations in the SLCO1B1 gene on the pharmacokinetics of lovastatin in a prospective genotype panel study. Seven healthy volunteers with the SLCO1B1*1B/*1B genotype, five with the SLCO1B1*5/*15 or *15/*15 genotype, and 15 with the SLCO1B1*1A/*1A genotype (controls) were recruited. Each study participant ingested a single 40-mg dose of lovastatin. Plasma concentrations of lovastatin (inactive lactone) and its active metabolite lovastatin acid were measured up to 24 h. In the SLCO1B1*5/*15 or *15/*15 genotype group, the geometric mean Cmax and AUC0-24 of lovastatin acid were 340 and 286% of the corresponding values in the SLCO1B1*1A/*1A (reference) genotype group (P<0.005). In contrast, the AUC0-24 of lovastatin acid in the SLCO1B1*1B/*1B genotype group was only 68% of that in the reference genotype group (P=0.03). No statistically significant association was observed between the SLCO1B1 genotype and the pharmacokinetics of lovastatin lactone. SLCO1B1*5/*15 and *15/*15 genotypes markedly increase the exposure to active lovastatin acid, but have no significant effect on lovastatin lactone, similar to their effects on simvastatin and simvastatin acid. Accordingly, it is probable that the risk of muscle toxicity during lovastatin treatment is increased in individuals carrying the SLCO1B1*5 or *15 allele. The SLCO1B1*1B/*1B genotype is associated with reduced lovastatin acid concentrations, consistent with enhanced hepatic uptake.

Effects of ezetimibe on the pharmacodynamics and pharmacokinetics of lovastatin

SUMMARYBackground: Ezetimibe is a cholesterol absorption inhibitor which decreases low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia. This study investigated the potential for pharmacodynamic and/or pharmacokinetic interactions between ezetimibe and lovastatin.Methods: In a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study, 48 healthy men with hypercholesterolemia (screening LDL-C ≥ 130 mg/dL) who were stabilized and maintained on a National Cholesterol Education Program (NCEP) Step I diet were randomized to one of the following six oral treatments once daily for 14 days: lovastatin 20 mg; lovastatin 20 mg plus ezetimibe 5, 10, or 20 mg; lovastatin 40 mg plus ezetimibe 10 mg; or placebo.Results: Reported adverse events were generally mild, nonspecific, and similar among treatments. There were no significant changes in safety laboratory test results, including those for enzymes indicative of muscle or liver injury. Co-administration of ezetimibe and lovastatin did not increase the plasma concentrations of lovastatin or β-hydroxylovastatin. In this parallel comparison study there was an apparent decrease in lovastatin exposure, however, the reduction in lovastatin or β-hydroxylovastatin concentrations was not related to the ezetimibe dose and is not considered to be clinically important. Ezetimibe 5, 10, or 20 mg combined with lovastatin 20 mg caused a significantly ( p < 0.01) greater reduction in LDL-C than lovastatin 20 mg alone, with no apparent effect on HDL-C or triglycerides. LDL-C was reduced by 51.0% with ezetimibe 10 mg plus lovastatin 20 mg, 56.0% with ezetimibe 10 mg plus lovastatin 40 mg, 33.2% with lovastatin alone, and 17.3% with placebo.Conclusions: The co-administration of ezetimibe and lovastatin was well tolerated and resulted in a significantly greater percentage reduction in serum LDL-C concentrations than with lovastatin alone, with an average incremental reduction of 16–18%. Ezetimibe 10 mg appears to be the optimal dose when co-administered with lovastatin 20 mg once daily. Further incremental reductions in LDL-C from the co-administration of ezetimibe and lovastatin are expected only when the dose of lovastatin is increased. The co-administration of ezetimibe and lovastatin has the potential to produce clinically significant reductions in LDL-C compared to either drug alone, with favorable safety and tolerability.

The effect of CYP2D6 genotype on the pharmacokinetics of lovastatin in Chinese subjects

To investigate whether specific CYP2D6 genotype can influence the pharmacokinetics of lovastatin, a drug with multi-metabolic pathway (CYP3A4, 2C9, 2D6 and hydrolysis). A single 40 mg oral dose of lovastatin was administered to 19 healthy subjects. Multiple blood samples were collected over 24 h, and plasma concentrations of lovastatin and lovastatin acid (one of the major metabolites by hydrolysis) were determined by an LC-MS-MS method. CYP2D6 genotype was determined using PCR followed by restriction enzyme analysis or allele-specific PCR tests. The subject distribution were: 4 homozygous CYP2D6*1 (*1/*1), 7 heterozygous CYP2D6*10 (*1/*10 or *2/*10) and 8 homozygous CYP2D6*10 (*10/*10) carriers. The area under the plasma concentration-time curve (AUC0–24) and terminal elimination half-life (t1/2) of lovastatin among the three groups were 12.4+4.0, 20.2+10.4 and 30.0+10.5 ng·h/ml, and 4.4+0.9, 6.0+2.4 and 8.1+2.5 h respectively (one-way ANOVA, p=0.022 for AUC0-24 and p=0.046 for t1/2). In comparison to the homozygous CYP2D6*1 carriers, the oral clearance of lovastatin were lower by 32.5% (p<0.05) and 55.2% (p<0.01) in the heterozygous CYP2D6*10 and homozygous CYP2D6*10 carriers respectively. The AUC0-24 of lovastatin acid also tended to be higher in the heterozygous CYP2D6*10 and homozygous CYP2D6*10 carriers; however, the difference was not statistically significant. These preliminary results in Chinese subjects show that among extensive metabolizers of CYP2D6, the pharmacokinetics of lovastatin appears to be dependent on CYP2D6 genotype. Clinical Pharmacology & Therapeutics (2004) 75, P18–P18; doi: 10.1016/j.clpt.2003.11.067

Effect of Colesevelam on Lovastatin Pharmacokinetics

To assess potential interactions of colesevelam hydrochloride and lovastatin in healthy volunteers when lovastatin alone was administered with dinner, both lovastatin and colesevelam were administered with dinner, and colesevelam was administered with dinner and lovastatin was administered 4 hours later with a snack. A single-center, open-label, 3-period, crossover drug interaction study was performed with 22 healthy volunteers. Blood samples were collected at specified intervals before and after dosing, and plasma concentrations of lovastatin and lovastatin hydroxyacid were measured using a liquid chromatography/mass spectroscopy/mass spectroscopy method. Maximal concentration (Cmax), AUC from time 0 to the last time point measured (AUC0-t), and AUC0-infinity values for lovastatin were 102%, 94%, and 104%, and for lovastatin hydroxyacid were 102%, 91%, and 92%, respectively, of control values when colesevelam and lovastatin were coadministered with dinner. Administration of colesevelam with dinner and lovastatin 4 hours later with a snack resulted in a decreased Cmax and AUC0-t for lovastatin (63% and 37%, respectively; p < 0.05) and an increased Cmax and AUC0-t for lovastatin hydroxyacid (61% and 50%, respectively; p < 0.05), both compared with lovastatin alone administered with dinner. Colesevelam had no significant effect on lovastatin pharmacokinetics when coadministered with lovastatin at dinner. A split-dosing regimen resulted in alterations in pharmacokinetic parameters for lovastatin and lovastatin hydroxyacid that are likely due to known differences in the pharmacokinetics of lovastatin when administered to patients with meals or in a fasting state.