Effects of torsemide on pharmacodynamics and pharmacokinetics of warfarin in humans and rats.

OBJECTIVES: This study aimed to evaluate the effects of torsemide on warfarin therapy in humans and rats. METHODS: For the animal study, rats were orally dosed with warfarin (0.13 mg/kg, control group) or warfarin (0.13 mg/kg) with torsemide (2 mg/kg, low dose group and 10 mg/kg, high dose group). The pharmacodynamic response of warfarin was assessed by measuring the international normalized ratio (INR) for 5 consecutive days following drug administration. For the human study, 191 patients on warfarin with mechanical heart valves were followed up retrospectively. The stable dose was calculated as the mean dose in INR levels of 2-3 for 3 consecutive times. KEY FINDINGS: In the animal study, the INR, maximum plasma concentration (Cmax ) and area under the plasma drug concentration-time curve (AUC0-∞ ) of (S)-warfarin in the high dose group were significantly higher than in other groups (P < 0.05). Compared with the control group, Cmax and AUC0-∞ of (R)-warfarin in the high and low dose groups were higher, whereas the volume of distribution/bioavailability and clearance/bioavailability were significantly lower (P < 0.05). In the univariate analysis of the clinical study, diuretics significantly lowered stable warfarin doses (P = 0.016) (5.07 ± 1.78 mg/day vs 5.77 ± 1.81 mg/day). After controlling confounding variables, the effects of diuretics were found to lower the warfarin dose by 0.464 mg. CONCLUSIONS: It was concluded that warfarin dose needs to be lowered when it is used concomitantly with diuretics.

Pharmacokinetic characteristics of capsaicin-loaded nanoemulsions fabricated with alginate and chitosan.

Nanotechnologies are being employed to enhance the stability and oral bioavailability of lipophilic substances, such as capsaicin. This study aimed to examine the pharmacokinetic properties of the formulated capsaicin-loaded nanoemulsions. A pharmacokinetic study was carried out using double-layer nanoemulsions fabricated with alginate and chitosan polymers and triple-layer nanoemulsions fabricated with chitosan/alginate polymers. Capsaicin nanoemulsions and capsaicin control (oleoresin capsicum) were administered to the rat at a dose of 10 mg/kg. A statistically significant difference was found in the area under the curve from time zero to time infinity (AUCinf) among formulations (p < 0.01). In comparison to the control group, the relative bioavailability of formulated nanoemulsions was up to 131.7. The AUCinf increased in a nano-size-dependent manner; as nano size decreased, AUCinf increased. IN comparison to the double-layer nanoemulsions, the triple-layer nanoemulsion showed a significantly increased volume of distribution, resulting in the increased clearance and decreased AUCinf. It was concluded that the formulated nanoemulsions could significantly enhance the bioavailabilty of capsaicin.

Effects of CYP4F2 gene polymorphisms on warfarin clearance and sensitivity in Korean patients with mechanical cardiac valves.

BACKGROUND: Recently, a single nucleotide polymorphism of CYP4F2 (rs2108622) was reported to have a significant relationship with the stable warfarin dose. However, the underlying mechanism of CYP4F2 effects on the stable warfarin dose has not been studied. This study aimed to examine the effects of cytochrome P450 (CYP) 4F2 gene on warfarin clearance and sensitivity in Korean patients with mechanical heart valves. METHODS: One hundred ninety-one patients with mechanical heart valves who were on anticoagulation therapy with warfarin and maintained international normalized ratio levels of 2-3 for 3 consecutive times were followed up, retrospectively. Warfarin enantiomer concentrations were determined by a validated high-performance liquid chromatography method. Genotypes of vitamin K epoxide reductase complex subunit 1, CYP2C9, CYP2C19, CYP4F2, human microsomal epoxide hydroxylase, calumenin, and γ-glutamyl carboxylase were determined. RESULTS: From multiple linear regression models, vitamin K epoxide reductase complex subunit 1, CYP2C9, CYP4F2, and age were found to have significant effects on warfarin stable dose. The stable warfarin daily doses of patients with the CC, CT, and TT genotypes in the CYP4F2 gene were 5.34 ± 2.04, 5.33 ± 1.64, and 6.55 ± 2.12 mg, respectively. The higher dose requirements in patients with TT alleles in CYP4F2 were attributable to a low warfarin sensitivity (international normalized ratio/warfarin plasma concentration); the warfarin sensitivity in CC, CT, and TT genotypes was 2.1 ± 1.2, 1.0 ± 0.4, and 0.8 ± 0.6, respectively. The similarity between the dose requirements of patients with CT and CC alleles was explained through the combined result of warfarin sensitivity and clearance outcomes. Apparent plasma (S)- and (R)-warfarin clearances were found to be 37.7% and 34.1% lower in CT genotype patients than in CC genotype patients, respectively. CONCLUSIONS: The dose variability in CYP4F2 genotypes was attributable to both warfarin clearance and sensitivity differences.