A study of the interaction of omeprazole and warfarin in anticoagulated patients.

1. Thirty-five patients on continuous therapy with warfarin were given omeprazole 20 mg once daily and placebo each for 3 weeks according to a two-centre randomised double-blind cross-over design. 2. Blood samples were obtained once weekly during the run-in and follow-up periods as well as during the first 2 weeks of each treatment period, and twice during the last week of each treatment period. Plasma concentrations of R- and S-warfarin were measured by h.p.l.c. and the anticoagulant effect was assessed using the Trombotest. 3. Twenty-eight patients were evaluated. The mean plasma concentration of R-warfarin was increased by 9.5% during omeprazole treatment compared with placebo, while that of S-warfarin, the more active isomer, was unaffected. The coagulation time was not significantly changed (106 s during omeprazole and 98 s during placebo). Corresponding TT-values (Trombotest) were 8.8 and 9.9 (NS).     

Quinidine single dose pharmacokinetics and pharmacodynamics are unaltered by omeprazole

Omeprazole has been shown in previous studies to inhibit the hepatic metabolism of selected drugs. Quinidine is an antiarrhythmic and antimalarial agent with a low therapeutic index. We therefore examined the effect of 40 mg omeprazole daily for one week or placebo on the pharmacokinetics and pharmacodynamics of a single 400 mg dose of quinidine in 8 healthy volunteers in a double-blind crossover study. During placebo and omeprazole treatment, there was no significant difference in area under the time-plasma quinidine concentration curve, (17.0 +/- 4.83 micrograms.h/ml, 18.6 +/- 4.43 micrograms.h/ml, respectively; P greater than 0.2) or renal clearance of quinidine (56.2 +/- 26.0 ml/min, 55.6 +/- 12.7 ml/min, respectively; P greater than 0.5). Quinidine unbound fraction in plasma (0.170 +/- 0.041 vs. 0.166 +/- 0.041 in the presence of omeprazole; P greater than 0.5) was not altered by omeprazole. Peak plasma quinidine concentration and the time this occurred did not differ. Omeprazole also had no effect on these parameters for the metabolite 3-hydroxyquinidine. There was no significant difference in the change in the corrected Q-T interval on the electrocardiogram due to quinidine (mean area under the time versus delta Q-Tc curve = 351 +/- 192 ms.h, placebo; 414 +/- 303 ms.h, omeprazole) showing that quinidine pharmacodynamics were unaltered by omeprazole. We conclude that omeprazole does not affect the pharmacokinetics of quinidine.     

Effect of tolterodine on the anticoagulant actions and pharmacokinetics of single-dose warfarin in healthy volunteers

This randomized, double-blind, crossover study investigated the potential effects of tolterodine ((R)-N,N-diisopropyl-3-(2-hydroxy-5-methyl-phenyl)-3-phenylpropanamine, CAS 124937-51-5), an antimuscarinic agent for the treatment of the overactive bladder, on the anticoagulant actions and pharmacokinetics of single-dose warfarin (CAS 81-81-2) in 20 healthy male volunteers. In terms of study design, volunteers randomly received oral tolterodine L-tartrate (2 mg twice daily) or matching placebo for 7 days, with a single oral dose of warfarin (25 mg) administered on day 4 of each treatment period. R-(+)- and S-(-)-warfarin pharmacokinetics were estimated from plasma levels measured up to 96 h post-dose, in conjunction with assessment of prothrombin time and factor VII activity. Pharmacokinetics of tolterodine and its active 5-hydroxymethyl metabolite ((R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethyl-phenyl)-3-phenylpropanamine; 5-HM), in the presence and absence of warfarin, were also determined. Relative to placebo, tolterodine had no discernible effect on the anticoagulant actions of warfarin. Point estimates of the tolterodine: placebo ratios for prothrombin time and factor VII activity were 1.00 (90% confidence interval [CI]: 0.91-1.10) and 0.91 (90% CI: 0.83-0.99), respectively, consistent with equivalence. No clinically significant changes in the pharmacokinetics of R-(+)- and S-(-)-warfarin were noted. Serum concentration-time profiles and the pharmacokinetics of tolterodine and 5-HM were similar in the presence and absence of warfarin. There were no safety concerns. These findings indicate that co-administration of tolterodine and warfarin is safe and well tolerated, with no clinically significant pharmacodynamic or kinetic interaction in healthy volunteers.     

Effect of the oral renin inhibitor aliskiren on the pharmacokinetics and pharmacodynamics of a single dose of warfarin in healthy subjects

AIMS: To investigate the effects of aliskiren, an oral renin inhibitor, on the pharmacokinetics and pharmacodynamics of warfarin. METHODS: In a single-blind, placebo-controlled, randomized, two-period crossover study, 15 healthy male and female subjects received a single oral dose of 25 mg racemic warfarin twice, once in the morning of the 8th day of treatment with 150 mg aliskiren and once at the same time point during treatment with placebo. Blood samples were collected for the measurement of prothrombin time (PT) and activated thromboplastin time (aPTT) and for determination of plasma concentrations of (R)- and (S)-warfarin. RESULTS: Aliskiren treatment had no effect on the blood coagulation parameters (PT, INR and aPTT). The ratios of least square means (90% CI) of pharmacokinetic parameters in the presence and absence of aliskiren for (R)- and (S)-warfarin were Cmax 0.89 (0.82, 0.96) and 0.88 (0.80, 0.97), AUC(0, infinity) 1.00 (0.94, 1.07) and 1.06 (0.96, 1.16) and t(1/2) 0.99 (0.92, 1.07) and 1.05 (0.96, 1.14). CONCLUSIONS: Multiple doses of aliskiren had no detectable effect on the pharmacokinetics or pharmacodynamics of a single dose of warfarin in healthy subjects.     

High clearance of (S)-warfarin in a warfarin-resistant subject.

A 30 year old black male required a 60 mg daily dose of warfarin to elicit a therapeutic anticoagulant response (normal warfarin dose 2.5-10 mg day-1; maximum 15 mg day-1). Hereditary warfarin resistance was suspected after compliance, diet, concurrent medication and any gastrointestinal disorder were eliminated as contributory causes. The disposition of vitamin K and vitamin K epoxide was examined in the propositus, his two sisters and 13 control black male subjects. Each subject was given an i.v. bolus dose (5 mg) of vitamin K prior to and after 2 weeks of warfarin therapy (5 mg day-1). The oral clearances of (S)- and (R)-warfarin were also measured in each subject during the last day of warfarin therapy. The mean (+/- s.d.) systemic clearance of vitamin K was similar in all subjects before (114 +/- 35 ml min-1) and after (112 +/- 40 ml min-1) warfarin therapy. The mean (+/- s.d.) AUC value for vitamin K epoxide was increased by warfarin treatment (6.5 +/- 5.4 micrograms ml-1 min before and 139 +/- 78 micrograms ml-1 min after) in all subjects. In the propositus, the oral clearance of (S)-warfarin (14.5 ml min-1) and the clearance ratio for (S)/(R)warfarin (2.6) differed by more than 7 standard deviations from the control group (4.3 +/- 1.1 ml min-1 and 1.2 +/- 0.2, respectively). In one sister of the propositus, the stereoselective disposition of warfarin was comparable with that of her brother ((S)-warfarin clearance = 16.2 ml min-1; and (S)/(R)-warfarin clearance ratio = 2.7).     

The pharmacokinetics and pharmacodynamics of single dose (R)- and (S)-warfarin administered separately and together: relationship to VKORC1 genotype

AIMS

1) To determine the pharmacokinetics and pharmacodynamics of (R)- and (S)-warfarin given alone and in combination and 2) to determine whether the relative potency of (R)- and (S)-warfarin is dependent on VKORC1 genotype.

METHODS

A three way crossover study was conducted in which 17 healthy male subjects stratified by VKORC1 1173 C>T genotype and all CYP2C9 1*/1* received (R)-warfarin 80 mg, (S)-warfarin 12.5 mg and rac-warfarin sodium 25 mg. Plasma (R)- and (S)-warfarin unbound and total concentrations and prothrombin time were determined at multiple time points to 168 h.

RESULTS

Pharmacokinetic parameters for (R)- and (S)-warfarin were similar to the literature. (R)-warfarin 80 mg alone resulted in a mean AUC_PT (0,168 h) of 3550 s h (95% CI 3220, 3880). Rac-warfarin sodium 25 mg containing (S)-warfarin 11.7 mg produced a greater effect on AUC_PT (0,168 h) than (S)-warfarin 12.5 mg (mean difference 250 s.h, 95% CI 110, 380, P < 0.002) given alone. In a mixed effects model the ratio of response between (R)- and (S)-warfarin (AUC_{PT((R)-warfarin)} : AUC_{PT((S)-warfarin)}) was 1.21 fold higher (95% CI 1.05, 1.41, P < 0.02) in subjects of VKORC1 TT genotype compared with the CC genotype.

CONCLUSIONS

(R)-warfarin has a clear PD effect and contributes to the hypoprothrombinaemic effect of rac-warfarin. VKORC1 genotype is a covariate of the relative R/S potency relationship. Prediction of drug interactions with warfarin needs to consider effects on (R)-warfarin PK and VKORC1 genotype.     

The role of cytochrome P2C19 in R-warfarin pharmacokinetics and its interaction with omeprazole

Previous studies reported omeprazole to be an inhibitor of cytochrome P450 (CYP) 2C19 and suggested the pharmacokinetic interaction of omeprazole with R-warfarin. The aim of this study was to compare possible effects of omeprazole on the stereoselective pharmacokinetics and pharmacodynamics of warfarin between CYP2C19 genotypes. Seventeen subjects, of whom 10 were homozygous extensive metabolizers (hmEMs) and seven were poor metabolizers (PMs) for CYP2C19, were enrolled in this randomized crossover study, and they ingested 20 mg omeprazole or placebo once daily for 11 days. On day 7, they administered a single dose of 10 mg racemic warfarin. The plasma concentrations of warfarin enantiomers and prothrombin time expressed as international normalized ratio were monitored up to 120 hours. During the placebo phase, area under the plasma concentration-time curve (AUC) and elimination half-life (t1/2) of R-warfarin in PMs was significantly greater than those in hmEMs (AUC[0-infinity], 42,938/34,613 ng h/mL [PM/hmEM], P = 0.004; t1/2, 48.8/40.8 hours [PM/hmEM], P = 0.013). Omeprazole treatment significantly increased the AUC(0-infinity) (41,387 ng h/mL, P = 0.004) and t1/2 (46.4 hours, P = 0.017) of R-warfarin in hmEMs to levels comparable to those in the PMs. There were no differences in S-warfarin pharmacokinetics between the CYP2C19 genotypes (AUC[0-infinity], 15,851/16,968 ng*h/mL [PM/hmEM]; t1/2, 22.7/25.4 h [PM/hmEM]), or between the two treatment phases (AUC[0-infinity], 14,756/18,166 ng h/mL [PM/hmEM]; t1/2, 27.0/25.4 hours [PM/hmEM] in the omeprazole phase) as well as anticoagulant effects. These results indicate that CYP2C19 activity was one of determinants on the R-warfarin disposition because the pharmacokinetics of warfarin enantiomers were different between the CYP2C19 genotypes and the omeprazole affected the R-warfarin pharmacokinetics of CYP2C19 in only hmEMs. However, the phamacodynamic effect of the interaction of warfarin with omeprazole would be of minor clinical significance.     

Different inhibitory effect of fluvoxamine on omeprazole metabolism between CYP2C19 genotypes

AIMS: Omeprazole is mainly metabolized by the polymorphic cytochrome P450 (CYP) 2C19. The inhibitory effect of fluvoxamine, an inhibitor of CYP2C19 as well as CYP1A2, on the metabolism of omeprazole was compared between different genotypes for CYP2C19. METHODS: Eighteen volunteers, of whom six were homozygous extensive metabolizers (EMs), six were heterozygous EMs and six were poor metabolizers (PMs) for CYP2C19, participated in the study. A randomized double-blind, placebo-controlled crossover study was performed. All subjects received two six-day courses of either daily 50 mg fluvoxamine or placebo in a randomized fashion with a single oral 40 mg dose of omeprazole on day six in both cases. Plasma concentrations of omeprazole and its metabolites, 5-hydroxyomeprazole, omeprazole sulphone, and fluvoxamine were monitored up to 8 h after the dosing. RESULTS: During placebo administration, geometric means of peak concentration (C(max)), under the plasma concentration-time curve from 0 to 8 h (AUC(0,8 h)) and elimination half-life (t(1/2)) of omeprazole were 900 ng ml(-1), 1481 ng ml(-1) h, and 0.6 h in homozygous EMs, 1648 ng ml(-1), 4225 ng ml(-1) h, and 1.1 h in heterozygous EMs, and 2991 ng ml(-1), 11537 ng ml(-1) h, and 2.8 h in PMs, respectively. Fluvoxamine treatment increased C(max) of omeprazole by 3.7-fold (95%CI, 2.4, 5.0-fold, P < 0.01) and 2.0-fold (1.4, 2.6-fold, P < 0.01), AUC(0,8 h) by 6.0-fold (3.3, 8.7-fold, P < 0.001) and 2.4-fold (1.7, 3.2-fold, P < 0.01), AUC(0, infinity ) by 6.2-fold (3.0, 9.3-fold, P < 0.01) and 2.5-fold (1.6, 3.4-fold, P < 0.001) and prolonged t((1/2)) by 2.6-fold (1.9, 3.4-fold, P < 0.001) and 1.4-fold (1.02, 1.7-fold, P < 0.05), respectively. However, no pharmacokinetic parameters were changed in PMs. The AUC(0,8 h) ratios of 5-hydroxyomeprazole to omeprazole were decreased with fluvoxamine in homozygous EMs (P < 0.05) and heterozygous EMs (P < 0.01). CONCLUSIONS: Even a low dose of fluvoxamine increased omeprazole exposure in EMs, but did not increase omeprazole exposure in PMs after a single oral dose of omeprazole. These findings confirm a potent inhibitory effect of fluvoxamine on CYP2C19 activity. The bioavailability of omeprazole might, to some extent, be increased through inhibition of P-glycoprotein during fluvoxamine treatment.     

Effect of omeprazole on the anticoagulant activity and the pharmacokinetics of warfarin enantiomers in rats

The effect of the proton pump inhibitor omeprazole on the anticoagulation and the pharmacokinetics of warfarin enantiomers was studied in rats. Omeprazole given intraperitoneally in a daily dose of 0.67 mg/kg over 8 days had no significant effect on the absorption, distribution and the total serum clearance values of the S- and R-enantiomers of warfarin. Omeprazole did not affect the pre-treatment baseline blood coagulation and the in vitro rat serum protein binding of warfarin enantiomers. In vitro study with rat liver microsomes showed that omeprazole had an inhibitory effect on the hydroxylation of warfarin enantiomers. Results obtained from in vivo urinary excretion study revealed that omeprazole inhibited the formation clearance of both S- and R-form oxidative metabolites, but increased that of the overall reductive metabolites, and the renal clearance of S- and R-enantiomers, of warfarin. As a consequence, the total serum clearance values for warfarin enantiomers remained unchanged and the hypoprothrombinaemic response produced by warfarin was not affected.     

Effect of modafinil at steady state on the single-dose pharmacokinetic profile of warfarin in healthy volunteers

Modafinil has been reported to produce a concentration-related suppression of CYP2C9 activity in vitro in primary cultures of human hepatocytes. To determine whether this effect occurs in vivo, the pharmacokinetics of (S)-warfarin was investigated after single oral doses of racemic warfarin (5 mg; COUMADIN) in a placebo-controlled, single-blind, single-period study in 28 volunteers. Subjects received an oral dose of warfarin prior to administration of modafinil (200 mg for 7 days, followed by 400 mg for 21 days) or placebo and they received another after 4 weeks of treatment. Treatment with modafinil did not significantly alter the pharmacokinetics of (S)- or (R)-warfarin relative to placebo. Since (S)-warfarin is predominantly metabolized via CYP2C9, the results indicate that the marked suppression of CYP2C9 activity in vitro does not translate into a similar effect clinically. However, limitations arising from investigation of single doses of warfarin preclude global conclusions about the potential for more subtle interactions after chronic warfarin administration.     

Study on warfarin plasma concentration and its correlation with international normalized ratio

A sensitive high-performance liquid chromatographic (HPLC) method was developed for warfarin determination in plasma of patients who undertook cardiac valve replacement and were on anticoagulation with warfarin. The method described proved to be accurate, sensitive, easy to perform, reproducible and specific for plasma warfarin measurement with relative standard deviation (R.S.D.) of <5.27% for inter-day and <6.89% for intra-day. The assay was linear in warfarin concentration ranges of 0.12-3 microg/ml (r=0.9995) with mean recovery of 94.6%. The mean warfarin plasma concentration of 58 patients with heart valve replacement within 1 month of post operation was 567.6+/-122.3 ng/ml. The anticoagulant effect of the drug was monitored by international normalized ratio (INR). The correlation of warfarin dosage and concentration with INR was analysed, and the coefficients were 0.21, 0.1相似文献   

Disposition of warfarin enantiomers and metabolites in patients during multiple dosing with rac-warfarin.

1. The disposition of warfarin enantiomers and metabolites has been studied in 36 patients receiving chronic rac-warfarin therapy, titrated to approximately the same anticoagulant response. 2. A stereoselective h.p.l.c. assay was employed to determine the concentrations of (R)- and (S)-warfarin, (R,S)-warfarin alcohol and (S)-7-hydroxywarfarin in plasma and 24 h urine samples. The concentrations of (R)-7-hydroxywarfarin, (S,S)-warfarin alcohol and (R)-6- and (S)-6-hydroxywarfarin were also determined in urine samples. The fractions unbound of warfarin enantiomers were determined using equilibrium dialysis. 3. Wide variability was observed in daily dose requirements (mean 6.1 mg; range: 2.5-12 mg), in plasma concentrations of (S)-warfarin (0.48 mg l(-1); 0.11-1.02 mg l(-1)), (R)-warfarin (0.87 mg l(-1); 0.29-1.82 mg l(-1)), (R,S)-warfarin alcohol (0.31 mg l(-1); 0.02-0.72 mg l(-1)) and (S)-7-hydroxywarfarin (0.25 mg l(-1); 0.07-0.37 mg l(-1)) and the percentage unbound of (S)-warfarin (0.53%; 0.29%-0.82%) and (R)-warfarin (0.54%; 0.26%-0.96%). 4. The mean plasma clearances of warfarin enantiomers were 7.5 1 day-1 per 70 kg (2.5-22.1) for (S)-warfarin and 3.6 1 day-1 per 70 kg (1.6-8.8) for (R)-warfarin. There was a significant correlation between the estimated formation clearance of (S)-7-hydroxywarfarin and the clearance of (S)-warfarin, which accounted for much of the variability in the latter.(ABSTRACT TRUNCATED AT 250 WORDS)     

A pharmacokinetic interaction study between omeprazole and the H2-receptor antagonist ranitidine

The effect of ranitidine pretreatment on the pharmacokinetics of omeprazole was investigated in 14 male human volunteers. Omeprazole (40 mg, gastroresistant pellets) was administered to the volunteers in a two-treatment study design, either alone or after 5 days pretreatment with b.i.d. doses of 150 mg ranitidine. Plasma concentrations of omeprazole were determined over a 24-hour period following drug administration, by a validated RP-HPLC method. Pharmacokinetic parameters were calculated with compartmental and non-compartmental analysis, using the computer program Kinetica (Inna Phase). In the two periods of treatments, the mean peak plasma concentrations Cmax were 730.8 ng/ml for omeprazole alone and 802.1 ng/ml for omeprazole co-administered with ranitidine (not significant). The time taken to reach the peak, Tmax, was 1.29 h and 1.42 h, respectively (not significant). The areas under the curve (AUC0-10) were 1,453.3 ng.h/ml and 1,736.8 ng.h/ml for the two periods of treatment; thus a greater AUC was obtained after pretreatment with multiple doses of ranitidine. Our data show that the pharmacokinetics of omeprazole might be inhibited by pretreatment with ranitidine; however, the clinical relevance of this interaction still has to be confirmed.     

心脏瓣膜置换术后患者使用质子泵抑制剂对华法林抗凝初期有效性及安全性的影响

目的：研究心脏瓣膜置换术后患者质子泵抑制剂（PPIs）对华法林抗凝初期的有效性及安全性的影响。方法：收集2013年1月至2014年12月在南京鼓楼医院行心脏瓣膜置换术后使用华法林联合PPIs的患者294例,根据术后使用PPIs的种类分为奥美拉唑组和泮托拉唑对照组。回顾性分析两组间PT值、INR值及华法林日剂量的差异,根据不良反应发生率及停药率评估PPIs与华法林联用的安全性。结果：两组间的华法林平均日剂量、INR值首次达标时间和住院期间INR的控制情况差异无统计学意义（P>0.05）。服药第1天和7天的INR值、PT值在两组间均无显著性差异（P>0.05）,第4天奥美拉唑组INR 1.84±0.49、PT（21.3±5.7）s,显著高于泮托拉唑组INR 1.71±0.37、PT（19.7±4.4）s,P<0.05。在INR 1.6~2.2亚组中,两组术后第4天的INR值分布存在显著性差异（P<0.05）。在安全性指标方面,奥美拉唑组的华法林停药率为（46.1%）,显著高于泮托拉唑组（25.25%）,INR>3的次数、栓塞率和出血率在两组间的差异均无统计学意义（P>0.05）。结论：心脏瓣膜置换术后的患者,在服用华法林抗凝的初期,奥美拉唑增强了华法林的抗凝效果,且影响华法林使用的安全性（如增加华法林的停药率）,两药联用时应当严密监测INR值,保证抗凝治疗的安全。     

Simultaneous determination of warfarin enantiomers and its metabolite in human plasma by column-switching high-performance liquid chromatography with chiral separation

A simple and sensitive column-switching high-performance liquid chromatographic method for the simultaneous determination of warfarin enantiomers and their metabolites, 7-hydroxywarfarin enantiomers, in human plasma is described. Warfarin enantiomers, 7-hydroxywarfarin enantiomers, and an internal standard, diclofenac sodium, were extracted from 1 mL of a plasma sample using diethyl ether-chloroform (80:20, v/v). The extract was injected onto column I (TSK precolumn BSA-C8, 5 microm, 10 mm x 4.6 mm inside diameter) for cleanup and column II (Chiralcel OD-RH analytical column, 150 mm x 4.6 mm inside diameter) coupled with a guard column (Chiralcel OD-RH guard column, 10 mm x4.6 mm inside diameter) for separation. The mobile phase consisted of phosphate buffer-acetonitrile (84:16 v/v, pH 2.0) for clean-up and phosphate buffer-acetonitrile (45:55 v/v, pH 2.0) for separation. The peaks were monitored with an ultraviolet detector set at a wavelength of 312 nm, and total time for chromatographic separation was approximately 25 minutes. The validated concentration ranges of this method were 3 to 1000 ng/mL for (R)- and (S)-warfarin and 3 to 200 ng/mL for (R)- and (S)-7-hydroxywarfarin. Intra- and interday coefficients of variation were less than 4.4% and 4.9% for (R)-warfarin and 4.8% and 4.0% for (S)-warfarin, and 5.1% and 4.2% for (R)-7-hydroxywarfarin and 5.8% and 5.0% for (S)-7-hydroxywarfarin at the different concentrations. The limit of quantification was 3 ng/mL for both warfarin and 7-hydroxywarfarin enantiomers. This method was suitable for therapeutic drug monitoring of warfarin enantiomers and was applied in a pharmacokinetic study requiring the simultaneous determination of warfarin enantiomers and its metabolite, 7-hydroxywarfarin enantiomers, in human volunteers.     

Pharmacokinetic interaction between warfarin and a uricosuric agent, bucolome: application of In vitro approaches to predicting In vivo reduction of (S)-warfarin clearance.

A uricosuric agent, bucolome, has been shown to intensify the anticoagulant effect of warfarin. The aims of the present study were to clarify its mechanism(s) and to apply in vitro approaches for predicting this potentially life-threatening in vivo interaction. An in vivo study revealed that Japanese patients given warfarin with bucolome (300 mg/day, n = 21) showed a 1.5-fold greater international normalized ratio than those given warfarin alone (n = 34) despite that the former received a 58% smaller warfarin dose than the latter. Enantioselective assays revealed that bucolome increased plasma unbound fractions of (S)- and (R)-warfarin by 2-fold (p <.01), reduced unbound oral clearances of (S)- and (R)-warfarin by 84 (p <.01) and 26% (p <.05), respectively, and inhibited the unbound formation clearance for (S)-warfarin 7-hydroxylation by 89% (p <.01). In contrast, bucolome elicited no appreciable changes in the plasma unbound (S)-warfarin concentration versus the international normalized ratio relationship. In vitro studies with recombinant human cytochrome P-450 2C9 and liver microsomes showed that bucolome was a potent mixed-type inhibitor for (S)-warfarin 7-hydroxylation, with K(i) of 8.2 and 20.2 microM, respectively. An in vitro model incorporating maximum unbound bucolome concentration in the liver estimated as a sum of hepatic artery and portal vein concentrations and in vitro K(i) made an acceptable prediction for bucolome-induced reductions in in vivo total (bound + unbound) oral clearance, unbound oral clearance, and unbound formation clearance for (S)-warfarin. In conclusion, the augmented anticoagulant effect of warfarin by bucolome due to the metabolic inhibition for pharmacologically more potent (S)-warfarin may be predictable from in vitro data.     

Validation of a method for the determination of (R)-warfarin and (S)-warfarin in human plasma using LC with UV detection

A sensitive and selective chiral high-performance liquid chromatography (HPLC) method was developed for the determination of (R)-warfarin and (S)-warfarin in human plasma. (R)- and (S)-warfarin and the internal standard (oxybenzone) were extracted from human plasma that had been made acidic with 1 N sulfuric acid into ethyl ether. The ethyl ether layer was removed and evaporated, and the residue was reconstituted in 200 microl of acetonitrile. A 50-microl aliquot was injected onto the HPLC system. Separation was achieved on a beta-cyclodextrin column (250 x 4.6 mm, 5 microm) with a mobile phase composed of acetonitrile:glacial acetic acid:triethylamine (1000:3:2.5, v/v/v). Detection was by ultraviolet absorbance at 320 nm. Late-eluting peaks were diverted from the analytical column by using a beta-cyclodextrin precolumn (50 x 4.6 mm, 5 microm) and a column switching device. The retention times of (R)- and (S)-warfarin and the internal standard were approximately 7.7, 6.9 and 4.0 min, respectively. The run time was 15 min. The assay was linear in concentration ranges of 12.5-2500 ng/ml for (R)- and (S)-warfarin in human plasma. The analysis of quality control samples for (R)- and (S)-warfarin (25.0, 400 and 2000 ng/ml) demonstrated excellent precision with relative standard deviations (R.S.D.) for (R)-warfarin of 10.9, 2.8, and 2.8%, respectively (n = 18), and for (S)-warfarin of 7.0, 2.4 and 2.6%, respectively (n = 18). The method was accurate with all overall (n = 18) mean concentrations being less than 6.0% from nominal at all quality control sample concentrations.     

Moexipril does not alter the pharmacokinetics or pharmacodynamics of warfarin

Summary The potential effect of moexipril, a new converting enzyme inhibitor, on the pharmacokinetics and pharmacodynamics of a single dose of warfarin has been investigated.Ten healthy male volunteers received in a randomised crossover fashion a single oral dose of 50 mg warfarin sodium alone and together with the first dose of 6 days of oral treatment with moexipril 15 mg o.d.Mean oral plasma clearance of (R)-warfarin was 175 ml·h^–1 in the absence and 181 ml·h^–1 in the presence of moexipril, and the corresponding values for (S)-warfarin were 248 ml·h^–1 and 249 ml·h^–1. Apparent volume of distribution, peak plasma concentration, time to reach peak concentration and area under the plasma concentration-time curve both of (R)- and (S)-warfarin were not significantly affected. Moexipril did not alter the maximum prothrombin time (20.3 versus 20.1 s, respectively in the absence and presence of moexipril), time to maximum response (48.0 versus 50 h) and area under the prothrombin time versus time curve.The results suggest that a clinically important interaction between moexipril and warfarin is unlikely to occur in patients treated with both drugs.     

The stereoselective effects of bucolome on the pharmacokinetics and pharmacodynamics of racemic warfarin

The objective of this study was to investigate the stereoselective influence of bucolome on the pharmacokinetics and pharmacodynamics of warfarin in Japanese inpatients with heart disease. Thirty patients were administered a fixed-maintenance dose of warfarin alone once a day for at least 7 days. The other 25 patients were concomitantly administered warfarin and a 300 mg dose of bucolome once a day, and blood samples were collected on days 1, 4, 7, 14, or 21 after administration of bucolome. Serum concentration of warfarin enantiomers was measured by a chiral reversed-phase HPLC-ultraviolet detection method. The PT-INR was used as a measure of the pharmacodynamic effect of warfarin. Coadministration of bucolome and warfarin had no effect on serum (R)-warfarin concentration and significantly increased serum (S)-warfarin concentration compared with warfarin alone. The PT-INR of warfarin alone was significantly lower with bucolome cotreatment. These results indicate that the augmented anticoagulant effect of warfarin by bucolome is due to inhibition of (S)-warfarin metabolism in vivo. When bucolome is added to a stabilized regimen of warfarin therapy, the dose of warfarin should be reduced by about 30% to 60%, and caution should be exercised during the first 7 days after coadministration of bucolome.     

Oral phenytoin pharmacokinetics during omeprazole therapy.

1. In a double-blind crossover study 10 healthy males received either placebo or omeprazole (40 mg day-1) for 9 days, a single dose of phenytoin (300 mg) being taken on the seventh day. 2. Omeprazole significantly increased the area under the curve (0 to 72 h) of phenytoin (mean +/- s.e. mean) from 121.6 +/- 14.0 to 151.4 +/- 13.6 micrograms ml-1 h) (P less than 0.01). 3. The peak concentration, and apparent elimination half-life of phenytoin also tended to be increased though not significantly. 4. The omeprazole-phenytoin interaction observed may be clinically important because of the low therapeutic index associated with phenytoin.