Pharmacokinetics and pharmacodynamics of rosiglitazone in relation to CYP2C8 genotype.
OBJECTIVE
Rosiglitazone is metabolically inactivated predominantly via the cytochrome P450 (CYP) enzyme CYP2C8. The functional impact of the CYP2C8*3 allele coding for the Arg139Lys and Lys399Arg amino acid substitutions is controversial. The purpose of this was to clarify the role of this polymorphism with regard to the pharmacokinetics and clinical effects of rosiglitazone.


METHODS
From a large sample of healthy volunteers, 14 carriers of the CYP2C8*1/*1 allele, 13 carriers of the *1/*3 allele, and 4 carriers the *3/*3 allele were selected for a clinical study. Rosiglitazone (8 mg) single-dose and multiple-dose pharmacokinetics and its effects on glucose level and body weight were monitored. Plasma and urine concentrations of rosiglitazone and desmethylrosiglitazone were measured, and kinetics was analyzed by noncompartmental and population-kinetic compartmental methods.


RESULTS
Mean total clearance values were 0.033 L x h(-1) x kg(-1) (95% confidence interval [CI], 0.030-0.037 L x h(-1) x kg(-1)), 0.038 L x h(-1) x kg(-1) (95% CI, 0.033-0.044 L x h(-1) x kg(-1)), and 0.046 L x h(-1) x kg(-1) (95% CI, 0.033-0.058 L x h(-1) x kg(-1)) in carriers of CYP2C8 genotypes *1/*1, *1/*3, and *3/*3, respectively, on day 1 (P = .02, ANOVA [F test]). Rosiglitazone kinetics could be adequately described by a 1-compartmental model with first-order absorption. Besides CYP2C8 genotype, body weight was a significant covariate (P < .001, log-likelihood ratio test). Elimination half-lives were 4.3, 3.5, and 2.9 hours in CYP2C8*1/*1, *1/*3, and *3/*3 carriers, respectively. Clearance of desmethylrosiglitazone was also higher in CYP2C8*3 allele carriers, with mean values of 1.96 L/h (95% CI, 1.42-2.69 L/h), 2.22 L/h (95% CI, 1.61-3.04 L/h), and 2.47 L/h (95% CI, 1.80-3.39 L/h), respectively (P = .03). The plasma glucose area under the concentration curve was significantly lower after 14 days of taking rosiglitazone compared with day 1 (P = .01, paired t test), but no relationship of the glucose-lowering effect of rosiglitazone with CYP2C8 genotype was observed.


CONCLUSIONS
This study showed that the CYP2C8*3 allele confers higher in vivo metabolic capacity than the wild-type CYP2C8*1 allele but the pharmacokinetic differences resulting from CYP2C8*3 were quantitatively moderate.
Kirchheiner
Julia
J
Institute of Pharmacology of Natural Products & Clinical Pharmacology, University of Ulm, Germany. julia.kirchheiner@uni-ulm.de
Thomas
Soju
S
Bauer
Steffen
S
Tomalik-Scharte
Dorota
D
Hering
Ursula
U
Doroshyenko
Oxana
O
Jetter
Alexander
A
Stehle
Simone
S
Tsahuridu
Martina
M
Meineke
Ingolf
I
Brockmöller
Jürgen
J
Fuhr
Uwe
U
D000483:Alleles; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001786:Blood Glucose / Q000187:drug effects; D065727:Cytochrome P-450 CYP2C8; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D010597:Pharmacogenetics; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology
D001786:Blood Glucose; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8