Paroxetine pharmacokinetics and molecular data

Pharmacokinetics and molecular data
Pharmacodynamics Pharmacokinetics
 * Absorption/distribution
 * Metabolism/excretion

Pharmacodynamics
The efficacy of Paroxetine in the treatment of major depressive disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD), and generalized anxiety disorder (GAD) is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically relevant doses in humans have demonstrated that Paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that Paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate that Paroxetine has little affinity for muscarinic, alpha1-, alpha2-, beta-adrenergic-, dopamine (D2)-, 5-HT1-, 5-HT2-, and histamine (H1)-receptors; antagonism of muscarinic, histaminergic, and alpha1-adrenergic receptors has been associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. Because the relative potencies of Paroxetine’s major metabolites are at most 1/50 of the parent compound, they are essentially inactive. Return to top

Pharmacokinetics
Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets of Paroxetine daily for 30 days. Paroxetine is extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of Paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers). Return to top

Absorption/distribution
Paroxetine is equally bioavailable from the oral suspension and tablet. Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30 days, steady-state Paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of Cmax, Tmax, Cmin, and T½ were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%), and 21.0 hours (CV 32%), respectively. The steady-state Cmax­ and Cmin values were about 6 and 14 times what would be predicted from single-dose studies. Steady-state drug exposure based on AUC0-24 was about 8 times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is a consequence of the fact that 1 of the enzymes that metabolizes Paroxetine is readily saturable. The effects of food on the bioavailability of Paroxetine were studied in subjects administered a single dose with and without food. AUC was only slightly increased (6%) when drug was administered with food but the Cmax was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours. Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma. Approximately 95% and 93% of Paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, Paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin. Return to top

Metabolism/excretion
The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of Paroxetine hydrochloride. In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled. Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of Paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of Paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in Paroxetine metabolism also suggests potential drug-drug interactions (see PRECAUTIONS). Approximately 64% of a 30 mg oral solution dose of Paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10 day post-dosing period. About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10 day post-dosing period. Return to top