Warfarin distribution

The distribution of the ionic species is determined by the molecular properties of the compound, but also by the nature and the concentration of the counterions present in the media [78]. For example, the influence of [Na ] on the transport kinehcs of warfarin through an octanol membrane has been reported [79]. 

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... 

Competition between drugs for plasma binding sites occurs and is responsible for some of the clinically most important changes in drug distribution. Phenylbutazone and oxyphenbutazone, for example, potentiate the action of warfarin by displacement (A2) and trichloroacetic acid, a major metabolite of chloral hydrate has a similar effect (S12) and is the cause of hemorrhagic complications during coumarin therapy (A2). 

Distribution - Valproic acid is rapidly distributed. Volume of distribution of total or free valproic acid is 11 or 92 L/1.73 m, respectively. Valproic acid has been detected in CSF (approximately 10% of total concentrations) and milk (about 1% to 10% of serum concentrations). Therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate. The plasma protein binding of valproate is concentration-dependent. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (eg, aspirin). Conversely, valproate may displace certain protein-bound drugs (eg, phenytoin, carbamazepine, warfarin, tolbutamide). 

Indirect response models have been successfully applied for a number of drugs that display a relatively slow onset of effect compared to their distribution to the site of action. Examples are corticosteroids, warfarin, furosemide and terbutalin. Such models are also particularly appropriate if the measured response is a change in circulating blood cells or endogenous proteins (e.g. hormones or cytokines). 

Warfarin is generally administered as the sodium salt and has 100% bioavailability. Over 99% of racemic warfarin is bound to plasma albumin, which may contribute to its small volume of distribution (the albumin space), its long half-life in plasma (36 hours), and the lack of urinary excretion of unchanged drug. Warfarin used clinically is a racemic mixture composed of equal amounts of two enantiomorphs. The levorotatory S-warfarin is four times more potent than the dextrorotatory R-warfarin. This observation is useful in understanding the stereoselective nature of several drug interactions involving warfarin. 

Even more subtle effects arise for drug interactions of a non-chiral drug with a chiral one. Phenylbutazone is not chiral in itself but it can interact with a chiral drug, warfarin, to change the activity of the latter. Phenylbutazone inhibits the oxidative metabolism of the (S)-(-) form of warfarin, (which is five times more potent than the (/ )-(+) form) and thereby decreases its clearance. Conversely, phenylbutazone induces the enzymatic reduction of the (/ ) form thus increasing the clearance.93 Analysis of total warfarin may indicate little departure from normal pharmacokinetics, but the distribution of eutomer and distomer will have changed markedly. 

To assess the potential for an interaction between raloxifene and warfarin, 15 healthy postmenopausal women each received single doses of warfarin 20 mg before and during 2 weeks of dosing with raloxifene 120 mg/day (37). Raloxifene reduced the oral clearance of R- and A -war-farin respectively by 7.1 and 14% and the oral volume of distribution by 7.4 and 9.8%. Raloxifene reduced the maximum prothrombin time by 10% and the area under the prothrombin versus time curve from 0-120 hours by an average of 8%. The authors concluded that raloxifene may produce a small increase in systemic warfarin exposure but a reduced pharmacodynamic effect. Since the effects are slight this interaction is unlikely to have clinical consequences. 

Yacobi, A. et al. Frequency distribution of free warfarin and free phenytoin fraction values in serum of healthy human adults. Clin Pharmacol Ther 1977, 21 283-286. 

Ultrafiltration has been used to determine the protein bound fraction of many drags, such as methadone (Wilkins et al. 1997), phenylacetate and phenylbu-tyrate (Boudoulas et al. 1996), etoposide (Robieux et al. 1997), doxorubicin and vincristine (Mayer and St-Onge 1995), disopyramide (Echize et al. 1995), and ketamine and its active metabolites (Hijazi and Boulieu 2002). Schumacher et al. (2000) have shown the applicability for the determination of erythro-cyte/plasma distribution. The method of UF has been applied in the measurement of free unaltered thyroxin or after displacement by salicylate as well after displacement by heparin in healthy people and in patients with non-thyroidal somatic illness (Faber et al. 1993). The protein binding of tritium labeled, antidiabetic repaglinide and its displacement by warfarin, furosemide, tolbutamide, diazepam, glibenclamide and nicardipine were determined by ultrafiltration (Plumetal. 2000). 

Protein binding Warfarin Plasma/liver distribution... 

Cigarette smoking altered the clearance and apparent volume of distribution of warfarin, although the net effect on anticoagulant activity was negligible both in volunteers (279) and patients (280). 

A patient taking warfarin and who had taken a decoction of S. miltiorrhiza presented with a prolonged bleeding time and melena (12) and other cases have been reported (13). Pharmacodynamic and pharmacokinetic studies in rats have shown that danshen increases the absorption rate constant, AUC, and half-lives of both R- and 5-warfarin, and reduces their clearances and apparent volumes of distribution (14,15). 

Warfarin is rapidly and nearly completely absorbed by the oral route. Peak plasma levels typically occur within 2-8 h. Warfarin is highly protein bound 97-99%. The volume of distribution approximates 0.151 kg Warfarin is extensively metabolized by hepatic microsomal enzymes. The primary metabolites are 6- and 7-hydroxy warfarin via oxidation and several warfarin alcohols via reduction. The warfarin alcohols retain weak anticoagulant activity. The metabolites undergo enterohepatic circulation. Approximately 85 % of warfarin appears in the urine as metabolites. Less than 1% or 2% appears in the urine unchanged. Warfarin metabolites are also excreted in the stool. The plasma half-life varies widely, from 10 to 80 h it is typically 36-44 h. The duration of clinical effects can significantly exceed the half-life of warfarin. (Note There are many drug interactions with warfarin the reader is referred to a standard pharmacology text for further details.)... 

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