Warfarin pharmacokinetics

Burke S, Amin N, Incerti C, Plone M, Watson N. Sevelamer hydrochloride (Renagel), a nonabsorbed phosphate-binding polymer, does not interfere with digoxin or warfarin pharmacokinetics. J Clin Pharmacol 2001 41(2) 193-8. 

Reynolds KK, Gage BF, Silvestrov NA, et al. Accuracy of genotype-based warfarin dose estimation and plasma S-warfarin pharmacokinetic modeling. Paper presented at the American Association of Clinical Chemistry Annual Meeting. Washington, DC 2008. 

Liao, S. Palmer, M. Fowler, C. Nayak, R.K. Absence of an effect of levofloxacin on warfarin pharmacokinetics and anticoagulation in male volunteers. J. Clin. Pharmacol. 1996, 36, 1072-1077. 

Reduced or increased metabolism. Sulfamethoxazole clearly inhibits the metabolism of warfarin by the cytochrome P450 isoenzyme CYP2C9, so enhancing its effect. Some macrolides such as erythromycin inhibit CYP3A4, and therefore have a minor inhibitory effect on warfarin, which would, on its own, be unlikely to be of any clinical relevance. Conversely, rifamycins , (p.375) are well established inducers of drug metabolism, and clearly reduce the effect of warfarin. Most other antibacterial classes have no effect on warfarin pharmacokinetics. 

In a double-blind, placebo-controlled study in 28 healthy subjects who were stabilised on warfarin, repaglinide did not alter the anticoagulant effects of warfarin or the steady-state warfarin pharmacokinetics. Therefore, no warfarin dosage adjustment would be anticipated on concurrent use. 

Not known. Based on in vitro data, both entacapone and tolcapone were thought to potentially interfere with the metabolism of drugs by the cytochrome P450 isoenzyme CYP2C9, such as 5-warfarin. " However, the above study shows that entacapone does not alter 5-warfarin pharmacokinetics, and tolcapone is also thought not expected to interact by this mechanism because it does not interact with tolbutamide , (p.516), another CYP2C9 substrate. 

Ovesen L, Lyduch S, Idom ML. The effect of a diet rich in hrussel sprouts on warfarin pharmacokinetics. EurJ Clin Pharmacol (1988) 33, 521-3. 

Sax MJ, Randolph WC, Peace KE, Chretien S,FrankWO,BraveimanAJ,GiayDR, McCree LC, Wyle F, Jackson BJ, Beg MA, Young MD. Effect of two cimetidine r imens on prothrombin time and warfarin pharmacokinetics during loi -terai war inther y. ClinPharm (1987)6,492-5. 

In a study, lasofoxifene caused a minor 16% decrease in prothrombin time without changing warfarin pharmacokinetics. 

Karim A Bradford D, Qian J, Hubbard R. The COX-2-specific inhibitor parecoxib sodium does not affect warfarin pharmacokinetic and pharmacodynamic parameters. American College of Emergency Physicians. Scientific Assembly, Chicago, Illinois, 15-18 October 2001. Abstract 130. 

Not understood. In one patient, renal impairment may have caused sulindac accumulation, which in turn may have affected warfarin pharmacokinetics. See also Coumarins and related drugs + NSAIDs , p.427. 

In pharmacological studies, omeprazole caused a minor increase in k-warfarin levels, with no or a minor increase in anticoagulant effect. Conversely, lansoprazole, pantoprazole and rabeprazole did not alter warfarin pharmacokinetics or anticoagulant effect Omeprazole does not appear to alter the effects of aeenoeoumarol and pantoprazole does not appear to later the effects of phenpro-coumon. Nevertheless, a number of isolated reports describe increased anticoagulant effects when PPIs are given with coumarins. 

Use of argatroban with warfarin and related oral anticoagulants has an effect on the measurement of the BVR, and the manufacturer provides equations to adjust for this. Argatroban does not alter warfarin pharmacokinetics. The manufacturers warn of the increased bleeding risks if aigatroban, bivalirudin or lepirudin are used with other anticoagulants. 

Vigilance for drug-drug interactions is required because of the greater number of medications prescribed to elderly patients and enhanced sensitivity to adverse effects. Pharmacokinetic interactions include metabolic enzyme induction or inhibition and protein binding displacement interactions (e.g., divalproex and warfarin). Pharmacodynamic interactions include additive sedation and cognitive toxicity, which increases risk of falls and other impairments. 

Dispositional antagonism occurs when one drug alters the pharmacokinetics (absorption, distribution, biotransformation, or excretion) of a second drug so that less of the active compound reaches the target tissue. Tor example, phenobarbital induces the biotransformation of warfarin, reducing its anticoagulant activity... 

Pharmacokinetic interactions Preliminary evidence suggests that Saint-John s-wort induces the cytochrome oxidase enzyme isoform CYP3A4 (Ernst 1999). This raises the potential for pharmacokinetic interactions with drugs metabolized by the same enzyme. A few cases have been reported of reduced warfarin levels (Yue et al. 2000). Similar interactions have also been reported for concurrent use with digoxin, theophylline, and cyclosporin (Nebel et al. 1999 Ruschitzka et al. 2000 Johne et al. 1999). As with any other medication, potential interactions should be considered when taking a combination of drugs. 

Toon S, Hopkins KJ, Garstang FM, et al. Comparative effects of ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of warfarin. Eur ] Clin Pharmacol 1987 32 165-72. 

Cimetidine, erythromycin, and dextropropoxyphene had no effect on the pharmacokinetics of MHD. Results with warfarin show no evidence of interaction with either single or repeated doses of oxcarbazepine. 

Bishydroxycoumarin (dicoumarol) is a natural occurring anticoagulant found in sweet clover. A number of coumarin derivatives have been synthesized as anticoagulants, warfarin, phenprocoumon and acenocoumarol being most frequently used. The nonpolar carbon substituent at the 3 position required for activity is asymmetrical. The enantiomers differ in both pharmacokinetic and pharmacodynamic properties. The coumarins are marketed as racemic mixtures. 

Clinicians should be aware of a few drug interactions with Zolpidem. Flumazenil acts as an antagonist to the hypnotic effects of zolpidem. There is decreased alertness when zolpidem is combined with cimetidine. There is an increase in anterograde amnesia in volunteers treated with a combination of imipramine and zolpidem. Haloperidol, ranitidine, chlorpromazine, warfarin, and digoxin, along with cimetidine and flumazenil, do not alter the pharmacokinetics of zolpidem (Salva and Costa, 1995). 

Jiang X, Williams KM, Liauw WS, et al. Effect of St John s wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 2004 57(5) 592-599. 

Zhou M, Chan KW, Ng LS, Chang S, Li RC. Possible influences of ginseng on pharmacokinetics and pharmacodynamics of warfarin in rats. J Pharm Pharmacol 1999 51 175-180. 

Lo ACT, Chan K, Yeung JHK, Woo KS. Dang gui (Angelica sinensis) affects the pharmacodynamics but not the pharmacokinetics of warfarin in rabbits. Eur J Drug Metab Pharmacokinet 1995 20 53-60. 

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