Drug distribution , volume hepatic disease

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). 

Fluoxetine is rapidly and completely absorbed orally, reaching a peak in 6-8 h. Food does not affect absorption. Fluoxetine is N-demethylated in the liver to an active metabolite, norfluoxetine, and many other minor inactive metabolites. Both fluoxetine and norfluoxetine are then conjugated prior to excretion. Protein binding is 94%. The volume of distribution is estimated to be 11-88.41 kg Approximately 2.5% of the drug is renally excreted unchanged and 10% as the norfluoxetine metabolite. A total of 65% of radiolabeled fluoxetine is recovered in the urine after 35 days and 15% is recovered in the feces. The elimination half-life of fluoxetine is 48-72 h, averaging almost 70 h. The half-life of norfluoxetine is 7-9 days. The elimination half-lives for both are prolonged in patients with hepatic disease. 

In the elderly, secondary to a decreased capacity for oxidation and alterations in the volume of distribution, drug accumulation can result. Patients with hepatic disease also are at risk for drug accumulation and subsequent complications. Therefore, intermediate- or short-acting benzodiazepines without active metabolites are preferred for chronic use in the elderly and those with liver disorders. Elderly patients are also sensitive to the CNS adverse effects of benzodiazepines (regardless of half-life) and their use is associated with a high frequency of falls and hip fractures. 

All three barbiturates are primarily eliminated by hepatic metabolism and renal excretion of inactive metabolites a small fraction of thiopental undergoes desulfuration to the longer-acting hypnotic pentobarbital. Each drug is highly protein bound (Table 13-2). Hepatic disease or other conditions that reduce serum protein concentration will decrease the volume of distribution and thereby increase the initial free concentration and hypnotic effect of an induction dose. 

B. Pharmacokinetics. Absorption may be delayed with sustained-release preparations. The volume of distribution (Vd) is approximately 0.5 Ukg. The normal elimination half-life is 4-6 hours this may be doubled by illnesses or interacting drugs that slow hepatic metabolism, such as liver disease, congestive heart failure, influenza, erythromycin, or cimetidine, and may increase to as much as 20 hours after overdose. (See also Table 11-59, p 381.)... 

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