The relationship between paroxetine and the sparteine oxidation polymorphism

Abstract

The relationship between the selective serotonin reuptake inhibitor paroxetine and the sparteine oxidation polymorphism was investigated in a combined single-dose (30 mg) and steady-state (30 mg/day for 2 weeks) study including a panel of nine extensive metabolizers and eight poor metabolizers of sparteine. The median area under the plasma concentration-time curve (AUC) after the first paroxetine dose was about seven times higher in poor metabolizers than in extensive metabolizers (3910 versus 550 nmol.hr/L), whereas at steady state the median AUCss tau interphenotype difference was only twofold (4410 versus 2550 nmol.hr/L). Plasma half-life and steady-state plasma concentration were significantly longer and higher, respectively, in poor metabolizers than in extensive metabolizers (41 versus 16 hours and 151 versus 81 nmol/L). Paroxetine pharmacokinetics were linear in poor metabolizers and nonlinear only in extensive metabolizers. Sparteine metabolic ratio (MR = 12 hour urinary ratio of sparteine/dehydrosparteine), increased during treatment with paroxetine in subjects who were extensive metabolizers, and after 14 days treatment two extensive metabolizers were phenotyped as poor metabolizers and the remaining extensive metabolizers were changed into extremely slow extensive metabolizers with sparteine MRs of 5.7 to 16.5. The inhibition of sparteine metabolism was rapidly reversed after cessation of paroxetine administration. In the poor metabolizers there were no significant changes in MRs during the study. It is concluded that paroxetine and sparteine metabolism cosegregates, but the interphenotype difference in metabolism was less prominent at steady state than after a single dose, presumably because of saturation of the sparteine oxygenase (CYP2D6) in subjects who were extensive metabolizers. Paroxetine is a potent inhibitor of sparteine oxidation by CYP2D6 in vivo.

A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia

“…29 Consequently, CYP2D6 is considered as a 'high affinity-low capacity' metabolic clearance pathway. 30 Consistent with this, the contribution of CYP2D6 to disposition of antipsychotics and other substrates is comparatively reduced during multiple [30][31][32][33][34] vs single-dose 31,35 drug administration. A considerable overlap in the distribution of antipsychotic serum concentration between EMs and PMs of CYP2D6 was also noted during chronic treatment.…”

Multiple Dose Pharmacokinetics of Paroxetine in Children and Adolescents with Major Depressive Disorder or Obsessive–Compulsive Disorder

“…In addition, it was shown that activity with respect to CYP2D6 phenotype could affect the exposure of paroxetine in children and adolescents (Findling et al, 1999). These phenomena have also been reported in adults (Ozdemir et al, 1999;Sindrup et al, 1992b) and are due to the involvement of the saturable enzyme CYP2D6 in paroxetine clearance.…”

Venlafaxine oxidation in vitro is catalysed by CYP2D6

“…PMs have no functional CYP2D6 enzyme as a result of mutations in the CY P2D6 gene. Interestingly, the phenotypic difference in paroxetine clearance is less after multiple dosing [6], presumably due to the development of inhibition and/or saturation of CYP2D6 in extensive metabolizers (EMS). CYP2D6 also makes a minor contribution to the N-demethylation of both enantiomers of fluoxetine, as indicated by studies using microsomes of human liver and of cells expressing CYP2D6 cDNA [ 131.…”

“…Two other SSRI agents, fluvoxamine and citalop-150 S. I/. Otton et al ram have K , values of 2 to 2 0 p~, and are weak inhibitors of CYP2D6 activity in uivo [ 10, 111. In addition to inhibiting CYP2D6, paroxetine is also metabolized by this enzyme [6,121 and the pharmacokinetics of paroxetine are altered in the 7% of Caucasians who are poor metabolizers (PMs). PMs have no functional CYP2D6 enzyme as a result of mutations in the CY P2D6 gene.…”