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Titolo:
Inhibition of cytochrome P4502D6 activity with paroxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline pharmacokinetics and the debrisoquin test
Autore:
Laine, K; Tybring, G; Hartter, S; Andersson, K; Svensson, JO; Widen, J; Bertilsson, L;
Indirizzi:
Univ Turku, Dept Pharmacol & Clin Pharmacol, FIN-20520 Turku, Finland UnivTurku Turku Finland FIN-20520 n Pharmacol, FIN-20520 Turku, Finland Huddinge Univ Hosp, Karolinska Inst, Dept Med Lab Sci & Technol, Div Clin Pharmacol, S-14186 Huddinge, Sweden Huddinge Univ Hosp Huddinge Sweden S-14186 col, S-14186 Huddinge, Sweden
Titolo Testata:
CLINICAL PHARMACOLOGY & THERAPEUTICS
fascicolo: 4, volume: 70, anno: 2001,
pagine: 327 - 335
SICI:
0009-9236(200110)70:4<327:IOCPAW>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
SPARTEINE OXIDATION POLYMORPHISM; SWEDISH POPULATION; POOR METABOLIZERS; CYP2D6 GENES; HYDROXYLATION; PLASMA; AMPLIFICATION; DEFECT; HUMANS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
28
Recensione:
Indirizzi per estratti:
Indirizzo: Laine, K Univ Turku, Dept Pharmacol & Clin Pharmacol, Kiinamyllynkatu 10, FIN-20520Turku, Finland Univ Turku Kiinamyllynkatu 10 Turku Finland FIN-20520 u, Finland
Citazione:
K. Laine et al., "Inhibition of cytochrome P4502D6 activity with paroxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline pharmacokinetics and the debrisoquin test", CLIN PHARM, 70(4), 2001, pp. 327-335

Abstract

Background: The ultrarapid metabolizer phenotype of the cytochrome P4502D6(CYP2D6) enzyme has been considered a relevant cause of nonresponse to antidepressant drug therapy. Prescribing high doses of antidepressants to suchpatients leads to high concentrations of potentially toxic metabolites andan increased risk for adverse reactions. Normalization of the metabolic status of ultrarapid metabolizers by inhibition of CYP2D6 activity could offer a clinically acceptable method to successfully treat such patients with antidepressants. Methods: Five ultrarapid metabolizers with a CYP2D6 gene duplication or triplication were treated with 25 mg nortriptyline twice a day for 3 consecutive weeks, alone during the first week and concomitantly with the CYP2D6 inhibitor paroxetine 10 mg or 20 mg twice a day, respectively, during the second and third weeks. After the third week, nortriptyline was discontinued and the subjects were treated with paroxetine 20 mg twice a day during the fourth study week. At the end of each study week, the steady-state pharmacokinetic parameters of nortriptyline or paroxetine were determined within thedose interval. In addition, the CYP2D6 phenotype was determined by debrisoquin (INN, debrisoquine) test at baseline and at the end of each study phase. Treatment-related adverse events were recorded during drug administration and for 1 week thereafter. Results. All 5 subjects had very low (subtherapeutic) nortriptyline concentrations after 7 days' treatment with nortriptyline only. Addition of paroxetine 10 mg twice a day to the nortriptyline regimen resulted in a change in all individuals to the "normal" extensive debrisoquine metabolizer phenotype, and therapeutic plasma nortriptyline concentrations were achieved in 4of 5 subjects after a 3 times mean increase in nortriptyline trough concentration (P = .0011). Doubling the paroxetine dose caused a 15 times mean increase in paroxetine trough concentration (P < .001), indicating strong inhibition by paroxetine of its own metabolism. The high paroxetine concentrations in 2 subjects caused them to have the poor debrisoquine metabolizer phenotype and resulted in a further increase in plasma nortriptyline trough concentration (P = .0099). A strong correlation (rank correlation coefficient [r(s)] = 0.89; P < .0001) was observed between paroxetine and nortriptyline trough concentrations. Paroxetine also significantly decreased the fluctuation of nortriptyline concentrations within the dose interval. One subject discontinued the study after the second study week because of adverse effects; otherwise, the study drugs were well tolerated. Conclusions: Paroxetine, with a daily dosage from 20 to 40 mg, is an effective tool in normalizing the metabolic status of CYP2D6 ultrarapid metabolizers.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/01/20 alle ore 19:27:06