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Pharmacokinetics and Pharmacodynamics of Warfarin

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Since warfarin is metabolized by hepatic cytochrome P-450 (CYP) isoenzymes predominately to inactive hydroxylated metabolites (excreted in the bile), warfarin metabolism may be altered in the presence of hepatic dysfunction or advanced age. It also is metabolized by reductases to reduced metabolites (warfarin alcohols), which are excreted by the kidneys. However, warfarin metabolism is not affected by renal impairment. (Stein JC, Olson KR, et al. This is because only small amounts of warfarin are excreted unchanged in urine. (Dewsbury C, 2003.After rapid intravenous or oral administration of an aqueous solution, warfarin has a distribution phase lasting 6 to 12 hours.

The estimates of the volumes of distribution of R- and S-warfarin are similar to each other and to that of the racemate. Approximately 99% of the drug is bound to plasma proteins. The volume of distribution (VD), also known as apparent volume of distribution, is defined as “ the volume in which the amount of drug would need to be uniformly distributed to produce the observed blood concentration” (Wikipedia). Warfarin has a VD of 8L, which reflects a high degree of plasma protein binding (Wikipedia).

Drugs like warfarin, which have an extensive plasma protein binding, tend to stay more in the central blood compartment, and have lower volumes of distribution. “ Albumin possesses a single strong binding site for warfarin. Binding to plasma albumin probably affects the duration and intensity of the action of a drug and protects the body against the full pharmacologic effect of the drug by temporarily inactivating it in a circulating reservoir that is in equilibrium with the unbound, active form of the drug. ” (OReilly RA, 1967.The warfarin-albumin interaction confines the drug molecules within the vascular space in an inactive form.

This prevents access to the sites of drug action, excretion, and metabolism. Therefore, warfarin sodium does not enter red blood cells, CSF is not present in the urine, and has a small volume of distribution that is identical to the albumin space.

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