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Andrew J Mclachlan - One of the best experts on this subject based on the ideXlab platform.
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pharmacodynamic interaction of Warfarin with cranberry but not with garlic in healthy subjects
British Journal of Pharmacology, 2009Co-Authors: M Mohammed I Abdul, Xuemin Jiang, Winston Liauw, Kenneth M Williams, Basil D. Roufogalis, Hongmei Xu, Andrew J MclachlanAbstract:Background and purpose: Patients commonly take complementary medicines in conjunction with Warfarin yet evidence supporting the safety or the risk of a herb–drug interaction is lacking. The aim of this study was to investigate the possible impact of two commonly used herbal medicines, garlic and cranberry, on the pharmacokinetics and pharmacodynamics of Warfarin in healthy male subjects. Experimental approach: An open-label, three-treatment, randomized crossover clinical trial was undertaken and involved 12 healthy male subjects of known CYP2C9 and VKORC1 genotype. A single dose of 25 mg Warfarin was administered alone or after 2 weeks of pretreatment with either garlic or cranberry. Warfarin enantiomer concentrations, INR, platelet aggregation and clotting factor activity were measured to assess pharmacokinetic and pharmacodynamic interactions between Warfarin and herbal medicines. Key results: Cranberry significantly increased the area under the INR–time curve by 30% when administered with Warfarin compared with treatment with Warfarin alone. Cranberry did not alter S- or R-Warfarin pharmacokinetics or plasma protein binding. Co-administration of garlic did not significantly alter Warfarin pharmacokinetics or pharmacodynamics. Both herbal medicines showed some evidence of VKORC1 (not CYP2C9) genotype-dependent interactions with Warfarin, which is worthy of further investigation. Conclusions and implications: Cranberry alters the pharmacodynamics of Warfarin with the potential to increase its effects significantly. Co-administration of Warfarin and cranberry requires careful monitoring. British Journal of Pharmacology (2008) 154, 1691–1700; doi:10.1038/bjp.2008.210; published online 2 June 2008
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Disposition of Warfarin enantiomers and metabolites in patients during multiple dosing with rac-Warfarin [see comments]
British Journal of Clinical Pharmacology, 1994Co-Authors: Eli Chan, Andrew J Mclachlan, M Pegg, Ad Mackay, Malcolm RowlandAbstract: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)
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Warfarin metabolites: Stereochemical aspects of protein binding and displacement by phenylbutazone
Chirality, 1993Co-Authors: Eli Chan, Andrew J Mclachlan, Malcolm RowlandAbstract:The in vitro human serum albumin binding characteristics of the enantiomers of the major metabolites of Warfarin [6-hydroxyWarfarin (6-HW), 7-hydroxyWarfarin (7-HW), (S)-Warfarin alcohols [(S,S)- and (S,R)-WA], and (R,S)-Warfarin alcohol [(R,S)-WA]] have been studied, using a stereospecific HPLC assay. Warfarin metabolites are less bound both within plasma and a 40 g/liter solution of human serum albumin than the enantiomers of Warfarin. The reduced Warfarin metabolites have a lower fraction unbound [1.33% for (S,R)-WA, 2.09% for (S,S)-WA, and 1.04% for (R,S)-WA] than hydroxylated metabolites [3.24% for (R)-6-HW, 4.26% (S)-6-HW, 4.49% for (R)-7-HW and 4.27% for (S)-7-HW] to HSA. Phenylbutazone produced a concentration-dependent increase in the unbound fraction of all metabolites. It was possible to predict the unbound fraction of Warfarin metabolites based on the unbound fraction of Warfarin enantiomers. © 1993 Wiley-Liss, Inc.
Diane K. Jorkasky - One of the best experts on this subject based on the ideXlab platform.
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eprosartan does not affect the pharmacodynamics of Warfarin
The Journal of Clinical Pharmacology, 1998Co-Authors: David J Kazierad, Bernard E Ilson, Steven C. Boike, Nevine Zariffa, Alan Forrest, David E Martin, Diane K. JorkaskyAbstract:Eprosartan is an angiotensin II receptor antagonist being developed for the treatment of hypertension and heart failure. The effect of eprosartan on the steady-state anticoagulant activity of Warfarin was evaluated in 18 healthy male volunteers. Each subject's daily Warfarin dose was titrated over 9 days to achieve a stable international normalized ratio (INR) of 1.3 to 1.6 by day 14. After the 14-day Warfarin titration phase, subjects were randomized to receive either eprosartan 300 mg or matching placebo twice a day for 7 days. All subjects continued to take the Warfarin dose established during the 14-day titration phase. The anticoagulant activity of Warfarin was statistically equivalent when coadministered with eprosartan or with placebo. No serious or unexpected adverse events suggestive of abnormal bleeding occurred during coadministration of eprosartan and Warfarin. As measured by the INR, there is no apparent effect of eprosartan on the anticoagulant effect of Warfarin.
Naohito Fujishima - One of the best experts on this subject based on the ideXlab platform.
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Drug interaction of (S)-Warfarin, and not (R)-Warfarin, with itraconazole in a hematopoietic stem cell transplant recipient.
Clinica Chimica Acta, 2011Co-Authors: Masatomo Miura, Naoto Takahashi, Syu-ichi Kanno, Shoutaro Kato, Miho Nara, Mitsugu Itoh, Hirobumi Saitoh, Tomoko Yoshioka, Yoshihiro Kameoka, Naohito FujishimaAbstract:Abstract Background Itraconazole is a potent inhibitor of CYP3A4 and P-glycoprotein, but not CYP2C9. Herein, we report a case study in which the plasma concentration of the CYP2C9 substrate ( S )-Warfarin, and not the CYP3A4 substrate ( R )-Warfarin, increased with itraconazole coadministration. Case A 67-y-old man received an allogenic bone marrow transplant for acute lymphoid leukemia. He was taking oral itraconazole (200 mg/day) and was started on a Warfarin dose of 2.0 mg/day. The plasma concentrations of ( S )- and ( R )-Warfarin 3 days after starting Warfarin administration were 216 and 556 ng/mL, respectively (INR 0.98), and after 10 days, the concentrations were 763 and 545 ng/mL, respectively (INR 2.43). On day 11 after withdrawal of itraconazole, the concentrations of ( S )- and ( R )-Warfarin were 341 and 605 ng/mL, respectively (INR 1.38). The concentration of ( R )-Warfarin was not affected by itraconazole; however, the final ( S )-Warfarin concentration had increased 7.3-fold. The ( S )-Warfarin/( S )-7-hydroxyWarfarin ratio decreased to 2.45 from 8.40 after discontinuation of itraconazole. The permeability of Warfarin enantiomers across Caco-2 cells was not influenced by itraconazole and showed no difference between enantiomers. Conclusions Careful INR monitoring is necessary for Warfarin co-administration with itraconazole. Further examination is necessary to elucidate mechanisms of the interaction between Warfarin and itraconazole.
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Drug interaction of (S)-Warfarin, and not (R)-Warfarin, with itraconazole in a hematopoietic stem cell transplant recipient.
Clinica Chimica Acta, 2011Co-Authors: Masatomo Miura, Naoto Takahashi, Syu-ichi Kanno, Shoutaro Kato, Miho Nara, Mitsugu Itoh, Hirobumi Saitoh, Tomoko Yoshioka, Yoshihiro Kameoka, Naohito FujishimaAbstract:Itraconazole is a potent inhibitor of CYP3A4 and P-glycoprotein, but not CYP2C9. Herein, we report a case study in which the plasma concentration of the CYP2C9 substrate (S)-Warfarin, and not the CYP3A4 substrate (R)-Warfarin, increased with itraconazole coadministration. A 67-y-old man received an allogenic bone marrow transplant for acute lymphoid leukemia. He was taking oral itraconazole (200mg/day) and was started on a Warfarin dose of 2.0mg/day. The plasma concentrations of (S)- and (R)-Warfarin 3 days after starting Warfarin administration were 216 and 556 ng/mL, respectively (INR 0.98), and after 10 days, the concentrations were 763 and 545 ng/mL, respectively (INR 2.43). On day 11 after withdrawal of itraconazole, the concentrations of (S)- and (R)-Warfarin were 341 and 605ng/mL, respectively (INR 1.38). The concentration of (R)-Warfarin was not affected by itraconazole; however, the final (S)-Warfarin concentration had increased 7.3-fold. The (S)-Warfarin/(S)-7-hydroxyWarfarin ratio decreased to 2.45 from 8.40 after discontinuation of itraconazole. The permeability of Warfarin enantiomers across Caco-2 cells was not influenced by itraconazole and showed no difference between enantiomers. Careful INR monitoring is necessary for Warfarin co-administration with itraconazole. Further examination is necessary to elucidate mechanisms of the interaction between Warfarin and itraconazole. Copyright © 2011 Elsevier B.V. All rights reserved.
Bruce Ritchie - One of the best experts on this subject based on the ideXlab platform.
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a randomized trial of restarting Warfarin at maintenance versus loading doses following an elective procedure
Journal of Thrombosis and Thrombolysis, 2017Co-Authors: Tammy J Bungard, Jay Mutch, Bruce RitchieAbstract:Guidelines suggest restarting Warfarin at known maintenance doses, although this may result in a delay to achieving therapeutic anticoagulation. As such, we compared the time to achieve an INR ≥ 2.0 between those restarting Warfarin maintenance vs loading doses after transient interruption, and the impact on protein C, S and factor II levels. Patients requiring interruption of Warfarin for elective procedures without hospitalization were randomized 1:1 to receive Warfarin maintenance or loading doses (1.5 times the maintenance dose for 3 days followed by pre-procedural Warfarin maintenance dosing). Protein C, S and Factor II were drawn at baseline (prior to Warfarin interruption), 7 and 14 days after restarting Warfarin. Among 19 patients randomized to maintenance and 20 to loading doses, nearly half in each group had mechanical heart valves with gastrointestinal endoscopic procedures most commonly performed (41%). The median number of days to reach an INR ≥ 2.0 was 7.8 days in the loading and 9.0 in the maintenance group (difference between medians 1.2 days, 95% CI −3.1 to 4.9; P = 0.19). Although levels of protein C, S and factor II were lower in the loading vs maintenance dose group, all remained above that of baseline. Warfarin resumption with loading doses shortened the time to achieve a therapeutic INR by a median of 1.2 days. Prompt Warfarin dose escalation should be done in response to the INR. Protein C and S remained above pre-Warfarin interruption levels, implying a lack of depletion with restarting Warfarin.
Jasper Dingemanse - One of the best experts on this subject based on the ideXlab platform.
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investigation of potential pharmacodynamic and pharmacokinetic interactions between selexipag and Warfarin in healthy male subjects
Clinical Therapeutics, 2016Co-Authors: Shirin Bruderer, Kaori Okubo, Hideya Mukai, Tim Mant, Jasper DingemanseAbstract:Abstract Purpose Selexipag is a new orally available nonprostanoid prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Warfarin is commonly used in patients with pulmonary arterial hypertension. Possible pharmacodynamic and pharmacokinetic interactions between selexipag and Warfarin in healthy individuals were investigated. Methods This was a double-blind, 2-way, 2-treatment crossover, Phase I study. Nineteen healthy men received a single dose of selexipag 400 μg or placebo on day 1, followed by selexipag 400 μg or placebo BID on days 2 to 12. A concomitant single dose of Warfarin 20 mg was administered in the morning of day 8. Findings Both treatments were well tolerated. The most frequently reported adverse event was headache in both treatments. Geometric mean ratios and 90% CIs of the maximum international normalized ratio (geometric mean ratio = 0.96; 90% CI, 0.90–1.03) and international normalized ratio AUC0–144h (geometric mean ratio = 0.98; 90% CI, 0.96–1.00)] during treatment with Warfarin and selexipag versus treatment with only Warfarin were inside the reference limits of 0.80 to 1.25. The 90% CIs of the geometric mean ratios of AUC and Cmax for R- and S-Warfarin during treatment with Warfarin and selexipag versus treatment with Warfarin alone were inside the reference range of 0.80 to 1.25. After repeated-dose administration of 400 μg selexipag, the AUC of selexipag and its active metabolite, ACT-333679, at steady state were not affected by a single dose of 20 mg Warfarin. Implications Steady-state levels of selexipag and ACT-333679 after repeated doses of 400 μg selexipag had no influence on the Warfarin pharmacodynamic variables. There was no pharmacokinetic interaction between selexipag and Warfarin.
