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Stereochemical aspects of warfarin drug interactions: Use of a combined pharmacokinetic‐pharmacodynamic model
Author(s) -
Chan Eli,
McLachlan Andrew,
O'reilly Robert,
Rowland Malcolm
Publication year - 1994
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1994.139
Subject(s) - pharmacodynamics , pharmacokinetics , warfarin , pharmacology , chemistry , volume of distribution , enantiomer , prothrombin time , phenylbutazone , medicine , stereochemistry , atrial fibrillation
Objective To apply a combined pharmacokinetic‐pharmacodynamic model to data from warfarin drug interaction studies. Methods The pharmacokinetic model for warfarin enantiomers combined a common first‐order absorption process with individual clearance and volume of distribution values and is based on unbound drug. The complete pharmacodynamic model comprised two components: that involving inhibition of pro‐thrombin complex activity (PCA) synthesis described by a sigmoid maximum effect (E max ) model and that relating temporal changes in PCA to synthesis and degradation. The combined model was applied to prothrombin time and plasma concentration‐time data obtained after oral administration of single doses of racemic warfarin to healthy subjects either alone or during multiple dosing with the metabolic enzyme inhibitor phenylbutazone or the inducer secobarbital. Results The five parameters associated with the complete pharmacodynamic model were k d (0.054 ± 0.014 hr −1 ), the degradation rate constant of PCA; Cu 50 , S (0.0026 ± 0.0015 mg • L −1 ) and Cu 50,R (3.45 ± 4.20 mg • L −1 ), the unbound concentrations of (S) ‐ and (R) ‐warfarin required to produce a 50% reduction in PCA synthesis if administered individually; γ (0.90 ± 0.23), the slope parameter in the sigmoid E max model; and t d (8.2 ± 0.3 hours), the observed delay in the onset of warfarin anticoagulant response. Conclusions These findings qualitatively confirm the known potency difference between warfarin enantiomers. Furthermore, although phenylbutazone and secobarbital altered the pharmacokinetics of warfarin, these compounds do not appear to influence its pharmacodynamics. Simulation studies indicate that, after racemate administration, the continual presence of the more potent ( S )‐enantiomer precludes accurate assessment of Cu 50 , R . Analysis indicates that use of racemic (rather than enantiomer) warfarin concentration data in drug interaction studies may lead to misinterpretation of pharmacodynamic data.