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Warfarin

15-70 hours

>4

^Data for rapid and slow acetylators are summarized from Table 4.4, Weber.12

^Data for rapid and slow acetylators are summarized from Table 4.4, Weber.12

research papers, and proceedings of conferences for this information, but even those sources may be insufficient for pharmacogenetic analysis.

Intersubject variability in the pharmacokinetics of a given drug is revealed by drug half-lives of several drugs in Table 3.2; 4- to 6-fold individual variability is common for many drugs widely used in medical therapy. Other pharmacokinetic parameters including those mentioned above also exhibit interindividual variability of a similar magnitude.

A pharmacokinetic variability of this magnitude is of clinical significance. For example, in a clinical trial involving Indian tuberculosis patients who had been treated with isoniazid for 1 year, genetically rapid acetylators responded much less satisfactorily than slow acetylators (60% of rapids vs. 82% of slows) by remaining bacteriologically positive longer, and relapsing more frequently because the rate of isoniazid inactivation by acetylation became important to its effectiveness. An impaired therapeutic effectiveness of the vasodilator drug hydral-azine, observed in rapid acetylators, was found to be due to the same mechanism as for isoniazid, i.e., lower systemic bioavailability resulting from greater first pass metabolism by phenotypically rapid acetylators compared to slow acety-lators; doses of hydralazine for rapid acetylators were up to 15 times larger than those required to achieve comparable effects in slow acetylators.12 Additional examples of pharmacokinetic variations that result in severe toxicity include the dramatic fall in blood pressure described for the poor debrisoquine metabolizer and the bone marrow suppression that occurs in slow methylators of thiopurines in leukemic children treated with 6-mercaptopurine.

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