Dosage clearance studies

A study in 8 AIDS patients taking itraconazole 200 mg daily found that when clarithromycin 500 mg twice daily was also given, for 14 days, the maximum serum levels and the AUC of the itraconazole were increased by 90% and 92%, respectively. Both clarithromycin and itraconazole are known to be metabolised by the hepatic cytochrome P450 isoenzyme CYP3A4 and it is therefore probable that competition for metabolism leads to a reduction in the clearance of itraconazole. This report does not comment on the outcome of this almost twofold increase in itraconazole levels, but it would seem prudent to be alert for the need to reduce its dosage. More study is needed. 

Numerous studies on the metabolism of 2,1t-dichlorophenoxy-acetic acid (2,1+-D) and related herbicides in animals have shown that these chemicals are absorbed and distributed rapidly in the body, and are excreted, undegraded, relatively quantitatively in the urine within a week after administration (M Pharmacokinetic studies with 2,1+,5-T in rats and dogs (5.) and in humans (6J supported these findings, and demonstrated that rates of clearance from plasma and elimination in urine depend on dosage level, animal species, and chemical structure of the phenoxy acid being studied ( + ). Corresponding chlorinated phenol metabolites were detected only in ruminants (M or in trace amounts in urine of rats fed very high doses of phenoxy herbicides (7.) ... 

Figure 2 Mean ( SE) plasma concentrations of triazolam (left) or alprazolam (right) in a series of healthy individuals who participated in a clinical pharmacokinetic study. In one phase of the study, they ingested a single 0.25-mg oral dose of triazolam with ketoco-nazole, 200 mg twice daily, or with placebo to match ketoconazole (control). In the second phase of the study, they took 1.0 mg of alprazolam orally, either with the same dosage of ketoconazole or with placebo to match ketoconazole (control). Note that ketoconazole increases AUC and reduces clearance of both triazolam and alprazolam. For triazolam (a high-extraction compound), the effect is evident as reduced presystemic extraction, increased Cmax, and prolonged half-life. However, for alprazolam (a low-extraction compound), the effect of ketoconazole is evident only as a prolongation of half-life. Abbreviation AUC, the plasma concentration-time curve. Source Adapted, in part, from Ref. 74.

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