Warfarin excretion

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... 

Warfarin is inactivated by hepatic P450 isozymes hydroxylated metabolites are excreted into the bile and then into the intestine. Hepatic disease may potentiate the anticoagulant response. 

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. 

Organochlorine insecticides are also well-known inducers. Treatment of rats with either DDT or chlordane, for example, will decrease hexobarbital sleeping time and offer protection from the toxic effect of warfarin. Persons exposed to DDT and lindane metabolized antipyrine twice as fast as a group not exposed, whereas those exposed to DDT alone had a reduced half-life for phenylbutazone and increased excretion of 6-hydroxy cortisol. 

Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified. Three of the human metabolites of donepezil have not undergone extensive safety tests in animals. These comprise two O-demethylated derivatives and an N-oxidation product. Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. The rate of metabolism of donepezil is slow and does not appear to be saturable. These findings are consistent with the results from formal pharmacokinetic studies which showed that donepezil and/or its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine, or digoxin... 

Sitaxsentan is a potent and selective agent which inhibits ET-1 binding to ETA receptors (IC50 = 1.4 nM), while being essentially inactive at ETB receptors (IC50 = 9.8 pM).23 In the clinic, it was found to have excellent oral bioavailability (70-100%) and a terminal elimination half-life of 10 h, and is administered as a once daily 100 mg dose. It is highly protein bound in plasma (> 99%) and extensively metabolized in the liver to inactive metabolites, predominantly by CYPs 2C9 and 3A4. Excretion is 50 60% renal, with the balance in the feces.25 Sitaxsentan inhibits CYP 2C9, and was observed to increase exposure to warfarin by over twofold. The use of cyclosporine A is also contraindicated, but no interactions were observed with sildenafil.15 Sitaxsentan was well tolerated in trials, with only minor side effects reported. Reversible liver enzyme abnormalities were also observed, but less frequently than with bosentan.15 25... 

The NADPH-dependent reduction of vitamin K quinone to the hydroquinone is not inhibited by warfarin. In the presence of adequate amounts of vitamin K, the carboxylation of glutamate residues can proceed normally, despite the presence of warfarin, with the stoichiometric formation of vitamin K epoxide that cannot be reutilized. Small amounts of vitamin K epoxide, and hydroxides formed by its reduction by other enzymes, are normally found in plasma. In warfarin-treated animals and patients, there is a significant increase in the plasma concentration of both. There is also an increase in the urinary excretion of the products of side-chain oxidation of the epoxide and hydroxides. 

Montelukast is extensively metabolized to 21- and 36-hydroxylated and dicarboxylic acid metabolites, which are excreted in the bile. The steady-state plasma concentrations of these metabolites are below the limit of detection in adults and children. In vitro studies have shown that high concentrations of montelukast inhibit CYP3A4 and CYP2C9, but in clinical studies the recommended dose of 10 mg/day did not interfere with metabolism of important cytochrome P450 substrates, such as warfarin (1). 

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.)... 

Drug metabolism may be influenced by stereochemical factors if the molecule in question possesses one or more chiral centres. Examples of drugs that show stereochemical differences in rates of metabolism include a-methyldopa (where the (S) isomer is decarboxylated more rapidly than the (R) isomer) and the enantiomers of warfarin, which are reduced at different rates. The well-known endogenous compound mevalonic acid (3,5-dihydroxy-3-methylpentanoic acid) is chiral and exists as two enantiomers. When a racemic mixture of mevalonic acid is fed to animals, one optical isomer is absorbed and metabolised, while virtually all of the other isomer is excreted by the kidneys into the urine. 

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