Pharmacokinetics And Distribution

Sertraline is absorbed slowly via the gastrointestinal tract, with peak plasma levels occurring between 6 and 8 hours after ingestion (Warrington 1991). The delay in achieving peak levels may be the result of enterohepatic circulation (Hiemke and Hartter 2000; van Harten 1993). When sertraline is taken with food, the peak level decreases to about 5.5 hours ("Zoloft" 2001). The medication is more than 95% protein bound; however, because it binds weakly to ai-glycoproteins, it does not cause substantial displacement of other protein-bound drugs (Preskorn 1996).

The volume of distribution (Vd) of sertraline is large in that it exceeds 20 L/kg. The distribution is larger in young females than in young males (Warrington 1991). In animal models, the concentration of sertraline is 40 times higher in brain than in plasma (Hiemke and Hartter 2000).

The elimination half-life of sertraline is 26-32 hours, and steady-state levels are achieved after 7 days. Sertraline shows linear pharmacokinetics within a range of 50-200 mg/day (Warrington 1991) and does not appear to inhibit or induce its own metabolism. Peak plasma levels are somewhat lower in young males, compared with females and older males (Ronfeld et al. 1997; Warrington 1991; "Zoloft" 2001), and the elimination rate constant is higher in young males than in females or older males (0.031/hour in young males; 0.022/hour in young females and 0.019/hour in older males and females).

In children between the ages of 6 and 17 years, weight-corrected metabolism is more rapid. The maximum concentration and area under the curve (AUC) are 22% lower than in adults. Despite the greater efficiency, the smaller body mass found in children suggests that lower dosages should be used ("Zoloft" 2001).

Sertraline is metabolized in the liver via oxidative metabolism; the concentration of the primary metabolite, desmethylsertraline, is up to threefold higher than that of the parent compound (Hiemke et al. 1991; Ronfeld et al. 1997; Warrington 1991). Desmethylsertraline levels are also lower in young males than in females and elderly males. The peak concentration (tmax) of desmethylsertraline is attained more quickly in young females than in young males (6 hours in young females vs. 9 hours in young males, 8 hours in older females, and 14 hours in older males) (Warrington 1991). The half-life of desmethylsertraline is 1.6-2.0 times that of the parent compound (Warrington 1991).

As mentioned above, desmethylsertraline is the major metabolite of sertraline; minor metabolites include a ketone and an alcohol compound (Warrington 1991). Less than 0.2% of an oral dose of sertraline is excreted unchanged in urine, whereas approximately 50% is found in feces. The enzymes involved in metabolism of sertraline to desmethylsertraline remain unclear (Greenblatt et al. 1999). Although six different CYP enzymes have the capacity to catalyze this reaction, none accounts for more than 25% of sertraline's clearance. The contribution of each CYP enzyme is dependent on not only the protein's activity on the substrate, as evidenced through in vitro models, but also the abundance of the enzyme. Given these properties, one computer model found that the greatest contribution to the demethylation of sertraline is from 2C9 (~23%), with 3A4 and 2C19 each contributing about 15%, 2D6 adding 5%, and 2B6 contributing 2% to the process (Greenblatt et al. 1999; Lee et al. 1999). The percentages could vary in a particular individual, depending on the amount of enzyme available or enzyme inhibition that occurs. However, given that multiple CYP enzymes are involved in this metabolic process, concurrent medications with specific CYP inhibition are not likely to impair metabolism of sertraline (Greenblatt et al. 1999).

Patients with liver disease experience decreased sertraline metabolism (Hiemke and Hartter 2000). For individuals with mild liver impairment, the half-life of drug may be increased threefold ("Zoloft" 2001). It is likely to be greater in patients with severe impairment, such as in those with cirrhosis. On the other hand, renal impairment does not appreciably influence the metabolism of sertraline (Hiemke and Hartter 2000).

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