Paroxetine pharmacokinetics

Paroxetine pharmacokinetics in 30 depressed children and adolescents of ages 6 to 17 demonstrated substantial interindividual variability and more rapid clearance in youths than in adults (Findling et ah, 1999). Nevertheless, paroxetine may be given once daily in the pediatric population. 

Lund, J., Thayssen, P., Mengel, H., Pedersen, O.L., Kristensen, C.B., and Gram L.F. (1982) Paroxetine pharmacokinetics and cardiovascular effects after oral and intravenous single doses in man. Acta Pharmacol Toxicol (Copenh) 51 351—357. 

Findling, R.L., Reed, M.D., Myers, C., Riordan, M.A., Fiala, S., Branicky, L., Waldorf, B., and Blumer, J.L. (1999) Paroxetine pharmacokinetics in depressed children and adolescents. / Am Acad Child Adolesc Psychiatry 38 952-959. 

Paroxetine 20 mg daily for 17 days, with atomoxetine 20 mg twice daily on days 12 to 17, was given to 22 healthy subjects who were extensive metabolisers of the cytochrome P450 isoenzyme CYP2D6 (most common phenotype). Paroxetine increased the AUC of atomoxetine 6.5-fold, increas l the maximum plasma level by 3.5-fold, and increased the elimination half-life by 2.5-fold, when compared with atomoxetine alone. No changes in paroxetine pharmacokinetics were seen. The pharmacokinetics of atomoxetine with paroxetine in these subjects was similar to that previously seen with atomoxetine alone in poor metaboliser subjects. 

Risperidone (11) was also included among a a 1-adrenergic receptor antagonists to study a quantitative structure-activity relationship (99BMC2437). A pharmacophore model for atypical antipsychotics, including 11, was established (00MI41). An increased plasma level of 11 and 9-hydroxyrisperidone (12) was observed in combination with paroxetine (01 MI 13). The effect of vanlafaxine on the pharmacokinetics of 11 was reported (99MI13). 

The pharmacokinetics of hyperforin have been studied in rats and humans (Biber et ai. 1998). In rats, after a 300 mg/kg orai dose of hypericum extract (WS 5572, containing 5% hyperforin), maximum piasma ieveis of 370 ng/mi (690 nM) are achieved at 3 hours. The haif-iife of hyperforin is 6 hours. Humans given a 300 mg tabiet of hypericum (containing 14.8 mg hyperforin) showed maximum piasma ieveis of 150 ng/mi (280 nM) at 3.5 hours. The haif-iife is 9 hours, and mean residence time is 12 hours. Pharmacokinetics of hyperforin are iinear up to 600 mg, and no accumuiation occurs after repeated doses. By comparison, effective and safe piasma ieveis of paroxetine and fluoxetine vary between 40 and 200 ng/mi (Preskorn 1997). The effective piasma concentration of hyperforin predicted from computer-fit data is approximateiy 97 ng/mi (180 nM), which couid be easiiy monitored (Biber et ai. 1998). There is a iinear correiation between orai dose of hyperforin and piasma ieveis, and steady-state concentrations of 100 ng/mi (180 nM) couid be achieved with three-times-daiiy dosing. 

Another practical example of a pharmacokinetic drug interaction concerns the incidence of seizures in patients given a standard (300 mg/ day) dose of clozapine. Should the patient be given an SSRI antidepressant (such as fluoxetine, fluvoxamine, sertraline or paroxetine) concurrently then the clearance of clozapine could be reduced by up to 50%, an effect which would be comparable with a doubling of the dose. This could lead to a threefold increase in the risk of the patient suffering a seizure. 

Elderly Clearance of fluvoxamine is decreased by about 50% in elderly patients. A lower starting dose of paroxetine is recommended. Sertraline plasma clearance may be lower. In 2 pharmacokinetic studies, citalopram AUC was increased by 23% and 30%, respectively, in elderly subjects as compared with younger subjects, and its half-life was increased by 30% and 50%, respectively. In 2 pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in elderly subjects as compared with young subjects and C ax was unchanged. 

Venkatakrishnan, K and Obach, R.S. (2005) In vitro-in vivo extrapolation of CYP2D6 inactivation by paroxetine prediction of nonstationary pharmacokinetics and drug interaction magnitude. Drug Metabolism and Disposition ... 

Venlafaxine, although its re-uptake inhibitory activity is not restricted to serotonin, is often classified as an SSRI because of its similar spectrum of adverse reactions. It has a short elimination half-life in contrast to the other serotonin re-uptake inhibitors. Fluoxetine, norfluoxetine and paroxetine are inhibitors of their own metabolism by CYP2D6 resulting in non-linear pharmacokinetic behavior. 

Preskorn S (1994) Targeted pharmacotherapy in depression management comparative pharmacokinetics of fluoxetine, paroxetine and sertraline. Int Clin Psychopharmacol 9(Suppl3) 13-19... 

Brookes AJ, Lehvaslaiho H, Siegfried M, et al (2000) HGBASE a database of SNPs and other variations in and around human genes. Nucleic Acids Res 28 356-360 Brosen K, Naranjo CA (2001) Review of pharmacokinetic andpharmacodynamic interaction studies with citalopram. Eur Neuropsychopharmacol 11 275-283 Brosen K, Hansen JG, Nielsen KK, Sindrup SH, Gram LF (1993) Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur J Clin Pharmacol 44 349-355... 

Alderman, J., Preskorn, S.H., Greenblatt, D.J., Harrison, W., Penen-berg, D., Allison, J., and Chung, M. (1997) Desipramine pharmacokinetics when coadministered with paroxetine or sertraline in extensive metabolizers. / Clin Psychopharmacol 17 284-291. 

Extrapyramidal side effects (EPS) associated with SSRI medications used as single agents were reported as early as 1979 (Meltzer et ah, 1979). Since then, several case reports have been published on use of fluoxetine (Elamilton and Opler, 1992), paroxetine (Nicholson, 1992), and sertraline (Opler 1994). The SSRI medications in combination with neuroleptics can cause severe EPS (Tate, 1989 Ketai, 1993) above and beyond what may be associated with increased levels of antipsychotic medications (Goff et ah, 1991), and are perhaps related to pharmacokinetic drug interactions. 

Wetzel H, Anghelescu 1, Szegedi A, et al Pharmacokinetic interactions of clozapine with selective serotonin reuptake inhibitors differential effects of fluvoxamine and paroxetine in a prospective study. J Clin Psy-chopharmacol 18 2-9, 1998... 

Adderall XR (package insert). Wayne, PA, Shire US Inc, 2004 Angrist B, d Hollosy M, Sanfilipo M, et al Central nervous system stimulants as symptomatic treatments for AIDS-related neuropsychiatric impairment. J Clin Psychophamiacol 12 268—272, 1992 Arnold LE, Lindsay RL, Connors CK, et al A douhle-hlind, placebo-controlled withdrawal trial of dexmethylphenidate hydrochloride in children with attention-deficit hyperactivity disorder. I Am Acad Child Adolesc Psychiatry 14 542—554, 2004 Belle DJ, Ernest CS, Sauer JM, et al Effect of potent CYP2D6 inhibition by paroxetine on atomoxetine pharmacokinetics. I Clin Pharmacol 42 1219-1227, 2002... 

Paroxetine at low concentration is dependent on CYP 2D6 for its clearance. However, this enzyme is almost completely saturated by paroxetine at low concentrations, which accounts for the nonlinear pharmacokinetics of paroxetine and why its half-life goes from 10 to 20 hours when the dose is advanced from 10 to 20 mg per day. At higher concentrations, paroxetine is most likely dependent on CYP 3A3/4 for its clearance. This dose-dependent change in the clearance of paroxetine probably accounts for the higher incidence of withdrawal reactions with this SSRI than might otherwise be expected for a drug with a half-life of 20 hours at steady-state on 20 mg per day (296, 297). 

Fluvoxamine, fluoxetine, and paroxetine have nonlinear pharmacokinetics, which means that dose increases lead to disproportionately greater increases in plasma drug levels (25). In contrast, citalopram and sertraline have linear pharmacokinetics. For these reasons, dose increases with fluvoxamine, fluoxetine, and paroxetine can lead to greater than proportional increases in concentration-dependent effects such as serotonin-mediated adverse effects (e.g., nausea) and inhibition of specific CYP enzymes. 

In comparison with TCAs, SSRIs cause fewer pharmacodynamic drug-drug interactions but some (i.e., fluvoxamine, fluoxetine, paroxetine) cause more CYP enzyme mediated pharmacokinetic drug-drug interactions. Unlike TCAs, SSRIs do not potentiate alcohol and perhaps even slightly antagonize its acute CNS effects. Nevertheless, there are some important adverse interactions. 

The most common interactions with SSRIs are pharmacokinetic interactions. For example, paroxetine and fluoxetine are potent CYP2D6 inhibitors (Table 30-4). Thus, administration with 2D6 substrates such as TCAs can lead to dramatic and sometimes unpredictable elevations in the tricyclic drug concentration. The result may be toxicity from the TCA. Similarly, fluvoxamine, a CYP3A4 inhibitor, may elevate the levels of concurrently administered substrates for this enzyme such as diltiazem and induce bradycardia or hypotension. Other SSRIs, such as citalopram and escitalopram, are relatively free of pharmacokinetic interactions. The most serious interaction with the SSRIs are pharmacodynamic interactions with MAOIs that produce a serotonin syndrome (see below). 

Several LC-MS and LC-MS/MS methods were developed in plasma for only one antidepressant and, sometimes, its major metabolite(s) to perform pharmacokinetic, bioavailability, or bioequivalence studies. Analytical methods developed for these purposes require very low LLOQ values and, usually, narrow linear ranges covering the low range of the therapeutic concentrations are validated. In this context, several methodologies were described for the determination of fluoxetine [94, 95, 98-100], paroxetine [44, 71, 85, 101, 102], venlafaxine [48, 61, 64, 86, 103,104], sertraline [62, 68, 83], citalopram [46, 89] and escitalopram [105], mianserine [106, 107], mirtazapine [42], trazodone [84], nefazodone [51, 81], duloxetine [47, 50, 73], and bupropion [43], Deuterated analogues of the analyte of interest or of other drugs were employed by few authors as IS [43, 61, 73, 81, 85, 99] however, in most of these methods, another antidepressant or other therapeutic drug was used for this purpose. 

Segura M, Ortuno J, Farre M et al (2003) Quantitative determination of paroxetine and its 4-hydroxy-3-methoxy metabolite in plasma by high-performance liquid chromatography/elec-trospray ion trap mass spectrometry application to pharmacokinetic studies. Rapid Commun Mass Spectrom 17 1455-1461... 

Hemeryck A, Lefebvre RA, De Vriendt C, et al. Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharmacol Ther 2000 67 283-291. 

Belle DJ, Ernest CS, Sauer JM, et al. Effect of potent CYP2D6 inhibition by paroxetine on atomoxetine pharmacokinetics. J Clin Pharmacol 2002 42 1219-27. 

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