Pharmacokinetics And Disposition

Paroxetine is well absorbed from the alimentary tract, and absorption is not affected by the presence or absence of food (Kaye et al. 1989). Being a highly lipophilic compound, paroxetine is readily distributed into peripheral tissues and exhibits a high volume of distribution, ranging from 3.1 to 28 L/kg (Kaye et al. 1989). Once absorbed, paroxetine is reportedly 95% bound to serum proteins (Kaye et al. 1989), though we have observed protein binding of 85% in our studies (M. J. Owens and C. B. Nemeroff, unpublished observations, June 1997). Oral bioavailability is affected by extensive first-pass metabolism, which is carried out by a high-affinity, low-capacity hepatic enzyme system (Lane 1996). With serial dosing, bioavailability increases as this metabolic system becomes saturated and a larger proportion of parent compound enters the systemic circulation (Kaye et al. 1989). Steady-state concentrations of paroxetine, following oral dosing, exhibit wide intersubject variability (Sindrup et al. 1992a). Following 30 days of daily administration of 30 mg of paroxetine, steady-state plasma concentrations ranged from 8.6 to 105 ng/mL (Kaye et al. 1989). Such variability has been considered inconsequential because a consistent relationship between paroxetine levels and clinical response or adverse outcome has not been found (see Tasker et al. 1989). However, higher plasma concentrations are associated with a greater magnitude of both 5 HTT and NET inhibition (Gilmor et al. 2002).

Strong in vivo and in vitro evidence points to the hepatic cytochrome P450 (CYP) 2D6 enzyme system as the rate-limiting mechanism in the metabolism of paroxetine (Crewe et al. 1992; Sindrup et al. 1992a). Genetic studies have demonstrated up to 40 polymorphisms of the 2D6 enzyme, which likely explain, at least in part, the wide-ranging differences in pharmacokinetic parameters observed among individuals (Lane 1996). Phenotypically, individual probands can be categorized as poor, extensive, or ultrarapid metabolizers and will have very high, low, or very low serum paroxetine concentrations, respectively (Charlier et al. 2003). Patients with negligible or diminished 2D6 activity are poor metabolizers of paroxetine and other 2D6-dependent substrates and are thought to use alternative enzyme systems (Gunasekara et al. 1998; Lane 1996). The 2D6 enzyme system is believed to be primarily responsible for the initial step in the metabolism of paroxetine in extensive and ultrarapid metabolizers, carrying out oxidation of the methylenedioxy bridge. The resulting unstable catechol intermediate is methylated and subsequently conjugated into polar compounds by the addition of a glucuronide or sulfate moiety and is then excreted into urine and feces (Haddock et al. 1989). These conjugated entities are the major circulating metabolites of paroxetine; however, unlike the metabolites of other SRIs, such as fluoxetine or sertraline, they exhibit minimal in vitro monoamine uptake inhibition and likely do not contribute any therapeutic activity (DeVane 1992; Haddock et al. 1989).

Paroxetine is the most potent inhibitor of the 2D6 enzyme system of all of the SRIs (Kj = 0.15 UM) (Crewe et al. 1992; Nemeroff et al. 1996). Studies in healthy volunteers show that the drug continues to cause meaningful inhibition of 2D6 up to 5 days postdiscontinuation (Liston et al. 2002). As both a substrate for and an inhibitor of its own metabolism, paroxetine has a nonlinear pharmacokinetic profile, such that higher doses produce disproportionately greater plasma drug concentrations as the enzyme becomes saturated and, therefore, less available for metabolic activity (Preskorn 1993). Peak plasma concentration is attained in approximately 5 hours, and plasma steady-state concentration is achieved within 4-14 days, following oral administration of paroxetine IR (Kaye et al. 1989). The terminal half-life (ty2) of the parent compound is approximately 1 day and increases at higher doses, consequent to autoinhibition of 2D6 (Preskorn 1993). The pharmacokinetic properties of paroxetine appear to be affected by age. Bayer et al. (1989) reported a threefold increase in maximum plasma concentration in elderly subjects, compared with younger subjects, following a single dose of paroxetine. Furthermore, ty2 in the elderly subgroup was extended by nearly 100%. Although there was significant overlap in both pharmacokinetic parameters between the age groups studied, the clinical principle of "start low and go slow" regarding medication treatment in older patients applies to paroxetine.

Patients with renal and hepatic insufficiency are often subject to alterations in metabolism and clearance of drugs, compared with healthy subjects. In individuals with renal impairment, both half-life and maximum plasma levels of paroxetine have been shown to increase relative to the extent of renal disease (Doyle et al. 1989). In a single-dose study, no significant difference was observed in pharmacokinetic outcomes in patients with cirrhosis of the liver, compared with healthy volunteers (Krastev et al. 1989); however, subsequent data revealed considerable elevations in steady-state concentration and ty2 of paroxetine following 14 days of administration of paroxetine in individuals with severe liver disease (Dalhoff et al. 1991). Accordingly, patients with substantial renal or hepatic dysfunction should initially be treated with a lower dose of paroxetine than is generally recommended to avoid potential side effects associated with unusually high plasma paroxetine levels.

Paroxetine CR was designed to slow absorption and delay the release of paroxetine until after the tablet has passed the stomach. The dissolution rate of paroxetine CR after single dosing is about 4-5 hours. It is completely absorbed and otherwise exhibits the same pharmacokinetic parameters with regard to ty2 and nonlinearity as the IR formulation. Following absorption, paroxetine CR is extensively distributed and highly protein bound. Paroxetine CR causes increased plasma concentrations of paroxetine in patients with renal and hepatic dysfunction, and lower doses are therefore recommended for these patients (Paxil CR 2002).

Paroxetine mesylate is a generic formulation of the compound in which a methanesulfonic acid moiety is attached to the compound during the salification process instead of the hydrochloric acid used in paroxetine hydrochloride. It is currently available in some European countries including Holland and

Denmark. Although currently there are no studies available comparing its efficacy or bioequivalence to paroxetine hydrochloride, there are several published case reports indicating problems of efficacy and tolerability in patients switched from paroxetine hydrochloride to paroxetine mesylate (Borgherini 2003) and this warrants further investigation.

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