Altered pharmacokinetics of R- and S-acenocoumarol in a subject heterozygous for CYP2C9*3.
OBJECTIVE
Our objective was to study the pharmacokinetics of R - and S -acenocoumarol in a subject who was highly sensitive to the anticoagulant effect of acenocoumarol. The subject was found to be heterozygous for CYP2C9*3.


METHODS
The plasma pharmacokinetics of the acenocoumarol enantiomers was established after an oral dose of 8 mg of racemic acenocoumarol. Urine was collected to establish the formation clearance of the 6- and 7-hydroxy metabolites of R - and S -acenocoumarol.


RESULTS
The pharmacokinetics of S -acenocoumarol in this subject differed greatly (oral clearance, 6%-10%; half-life of elimination, 400%-500%) from the values of a [wt/wt] control and from population values. R -acenocoumarol clearance was at the lower level of population values. The apparent formation clearances of the metabolites were low-approximately 10% of control activity for the hydroxylations (6- and 7-) of S -acenocoumarol and for the 7-hydroxylation of R -acenocoumarol. The rate of the 6-hydroxylation of R -acenocoumarol was about 50% of control values.


CONCLUSIONS
The presence of even one copy of CYP2C9*3 reduces profoundly the metabolic clearance of S -acenocoumarol. As a result the first-pass effect of elimination is abolished and the maintenance time is increased. S -Acenocoumarol, which is normally clinically inactive, will now exert main anticoagulant activity.
Thijssen
H H
HH
Department of Pharmacology, Cardiovascular Research Institute, University of Maastricht, The Netherlands. h.thijssen@farmaco.unimaas.nl
Drittij
M J
MJ
Vervoort
L M
LM
de Vries-Hanje
J C
JC
D000074:Acenocoumarol / Q000493:pharmacokinetics*; D000293:Adolescent; D000483:Alleles; D000925:Anticoagulants / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D002851:Chromatography, High Pressure Liquid; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004342:Drug Hypersensitivity / Q000503:physiopathology; D005091:Exons / Q000235:genetics; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D013237:Stereoisomerism; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*
D000925:Anticoagulants; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; D000074:Acenocoumarol