Publications (12) View all
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Article: Simultaneous determination of risperidone and 9-hydroxyrisperidone enantiomers in human blood plasma by liquid chromatography with electrochemical detection.
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ABSTRACT: Risperidone is a commonly prescribed antipsychotic drug. An enantioselective HPLC method with electrochemical detection was developed and validated for simultaneous determination of plasma concentrations of risperidone and its active metabolites, 9-hydroxyrisperidone enantiomers. Following solid phase extraction of 1.0 mL blood plasma, a baseline separation of the analytes was achieved on an AGP (alpha1 acid glycoprotein) column using isocratic mobile phase consisting of methanol-phosphate buffer (pH 6.2; 0.1 M) (15:85, v/v). Total analysis run time was 11 min. For the detection of the analytes analytical cell potentials were set at 500, 650, 950, and 950 mV. The method linearity was attained in the range from 1.0 to 100 ng/mL for risperidone and both 9-hydroxyrisperidone enantiomers. The limit of detection was 0.5 ng/mL for all three analytes. The method was precise and accurate and was successfully applied in a clinical study investigating the stereoselectivity of risperidone 9-hydroxylation.Journal of pharmaceutical and biomedical analysis 07/2009; 50(5):905-10. · 2.45 Impact Factor -
Article: Gastric emptying of pellets under fasting conditions: a mathematical model.
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ABSTRACT: To develop a mathematical model that would adequately describe human gastric emptying of pellets under fasting conditions of healthy subjects. Scintigraphic profiles representing the gastric emptying of pellets were obtained from the literature. Altogether 19 individual and three mean scintigraphic profiles were collected. Three mathematical models namely; the lag-time exponential (two parameters), the Weibull (two parameters), and the double Weibull (five parameters) model were proposed and fitted to the gastric emptying profiles. Different patterns of gastric emptying (immediate and rapid, delayed but rapid, delayed and slow, and interruptive emptying) were observed, with the emptying time varied from approximately 15 min to more than 3 h. The best model for fitting to the individual profiles was the double Weibull model. This model also provided an insight into the mechanism of interruptive emptying of pellets, observed for some patients. In addition, mean gastric emptying of pellets was calculated using the Weibull model. Mean gastric emptying of pellets was adequately described by the Weibull model (eta = 61.9 min, beta = 0.895), which could be applied in the design of in vitro dissolution experiments for pellet formulations with pH dependent dissolution.Pharmaceutical Research 05/2009; 26(7):1607-17. · 4.09 Impact Factor -
Article: Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose.
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ABSTRACT: Warfarin is an anticoagulant drug with narrow therapeutic index and high interindividual variability in dose requirement. S-warfarin is metabolized mainly by polymorphic cytochrome P450 (CYP) 2C9. We systematically quantified the influence of CYP2C9 genotype, demographic factors and concomitant drug treatment on warfarin metabolism and maintenance dose. The mean warfarin doses were lower in carriers of one (2.71 mg/day, 59 patients) and two polymorphic alleles (1.64 mg/day, 11 patients) than in carriers of two wild-type alleles (4.88 mg/day, 118 patients). Multiple regression analysis demonstrated that CYP2C9 genotype, age, concomitant treatment with warfarin metabolism inducers and lean body weight contributed significantly to interindividual variability in warfarin dose requirement (adjusted R(2)=0.37). The same factors, except for age, significantly influenced S-warfarin clearance (adjusted R(2)=0.42). These results can serve as a starting point for designing prospective studies in patients in the initiation phase of genotype-based warfarin therapy.The Pharmacogenomics Journal 02/2005; 5(3):193-202. · 4.54 Impact Factor -
Article: The influence of co-treatment with carbamazepine, amiodarone and statins on warfarin metabolism and maintenance dose.
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ABSTRACT: Warfarin is a frequently used anticoagulant drug with narrow therapeutic index and high interindividual variability in the dose requirement. We have previously shown that warfarin dose is influenced by cytochrome P450 (CYP) 2C9 genotype, age, body weight and co-treatment with drugs that interfere with warfarin metabolism. As, in many patients, drug co-treatment cannot be avoided, we investigated the effect of co-treatment with carbamazepine, amiodarone and statins on warfarin metabolism and maintenance dose. Caucasian patients on stable maintenance warfarin therapy with CYP2C9*1/*1 genotype (n=82) were included in the study. Plasma concentrations of (S)- and (R)-warfarin as well as warfarin hydroxylated metabolites were determined using HPLC assay and corresponding clearances of (S)- and (R)-warfarin were calculated. Patients co-treated with carbamazepine (n=5) had significantly higher plasma 10-hydroxywarfarin concentrations than patients not taking any interacting drugs (n=54) (median: 0.327 microg/ml vs 0.030 microg/ml, p=0.003). (S)- and (R)-warfarin clearances were also higher in the carbamazepine co-treated group (p=0.003), as were warfarin dose requirements (median: 9.00 mg/day vs 3.86 mg/day, p=0.003). Under the conditions of this study, patients co-treated with amiodarone (n=6) did not differ significantly regarding any measured characteristic from patients with no interacting drug treatment, while patients co-treated with simvastatin or lovastatin (n=17) had lower 10-hydroxywarfarin concentration (p=0.02). We confirmed important interaction between carbamazepine and warfarin metabolism which can be of major clinical importance. If treatment with carbamazepine cannot be avoided, patients taking warfarin should be frequently monitored, especially when initiating or stopping carbamazepine therapy.European Journal of Clinical Pharmacology 05/2006; 62(4):291-6. · 2.85 Impact Factor -
Article: Determination of warfarin enantiomers and hydroxylated metabolites in human blood plasma by liquid chromatography with achiral and chiral separation.
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ABSTRACT: An assay comprising two simple, selective and isocratic HPLC methods with UV detection was developed and validated for measuring warfarin enantiomers and all five warfarin monohydroxylated metabolites in patient blood plasma. Following liquid/liquid extraction from 1 ml of blood plasma a baseline separation of analytes was achieved on chiral (alpha(1) acid glycoprotein - AGP) and achiral (C(18)) column. Both methods were consistent (R.S.D.<6.9% for warfarin enantiomers and<8.9% for monohydroxylated metabolites) and linear (r>0.998). The limits of detection were 25 ng/ml for warfarin enantiomers, 25 ng/ml for 4'-, 10-, 6- and 7-hydroxywarfarin, 35 ng/ml for 8-hydroxywarfarin and 50 ng/ml for racemic warfarin. In a clinical study in 204 patients, it was confirmed that the assay is appropriate for evaluation of influences of genetic polymorphisms, demographic factors and concomitant drug treatment on warfarin metabolism.Journal of Chromatography B 05/2005; 818(2):191-8. · 2.89 Impact Factor
