Nortriptyline pharmacokinetics

Laine K, TybringG, Harder S, etal. Inhibition of cytochrome P4502D6 activity with paroxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline pharmacokinetics and the debrisoquin test. Clin Pharmacol Ther 200l 70( 4) 327 35. 

Wong SL, Cavanaugh J, Shi H, Awni WM, Granneman GR. Effects of divalproex sodium on amitriptyline and nortriptyline pharmacokinetics. Clin Pharmacol Ther 996) 60, 48-53. 

Note Derivatization with this reagent sequence in combination with extraction and TLC separation is speciftc for amitriptyline and nortriptyline in the analysis of plasma furthermore its high sensitivity allows its employment in pharmacokinetic studies, e. g. after the oral administration of a single dose of 25 mg amitriptyline. 

Yue, Q.Y. et al. (1998). Pharmacokinetics of nortriptyline and its 10-hydroxy metabolite in Chinese subjects of different CYP2D6 genotypes. Clin. Pharmacol. Ther., 64, 384-90. 

Compared to antipsychotics, there are even fewer studies on the prescribing patterns of antidepressants done in Asian countries. Pi etal. (1985) conducted a survey of psychotropic prescribing practices reported by psychiatrists in 29 medical schools in 9 Asian countries. Daily dose range of tricyclic antidepressants (TCAs) such as amitriptyline, imipramine, and nortriptyline in Asian countries was comparable to the practice in USA. This is despite differences found between Asian and non-Asian populations in the pharmacokinetics of TCAs (Pi et al, 1993). A questionnaire on the practical prescribing approaches in mood disorders administered to 298 Japanese psychiatrists was reported by Oshima et al. (1999). As first-line treatment, the majority of respondents chose newer TCAs or non-TCAs for moderate depression and older TCAs for severe depression. Combination of antidepressants and anxiolytics was preferred in moderate depression, while an antidepressant and antipsychotic combination was common in severe psychotic depression. Surprisingly, sulpiride was the most favored drug for dysthymia. In a naturalistic, prospective follow-up of 95 patients with major depression in Japan, the proportion of patients receiving 125 mg/day or less of imipramine was 69% at one month and 67% at six months (Furukawa et al., 2000). 

Merle, Y. and Mentre, F. (1999) Optimal sampling times for Bayesian estimation of the pharmacokinetic parameters of nortriptyline during therapeutic drug monitoring. / Pharmacokinet Biopharm 27 85-101. 

Geller B, Cooper TB, Graham DL, et al. Pharmacokinetically designed double-blind placebo-controlled study of nortriptyline in 6 to 12 year-olds with major depressive disorder. J Am Acad Child Adolesc Psychiatry 1992 31 34-44. 

Much of the study of interethnic differences in the pharmacokinetics and pharmacodynamics of psychotropic medications has involved TCAs and differences between Asians and Caucasians (Pi et al. 1993a). As with antipsychotics, there are clinical reports that Asians require lower doses of TCAs (Pi and Gray 1998 Pi et al. 1993a). It has also been suggested that Asians show a therapeutic response at lower blood levels of TCAs (Yamashita and Asano 1979), suggesting pharmacodynamic differences. Other studies of prescribing patterns have failed to confirm this and found that the daily doses of amitriptyline, imipramine, doxepin, and nortriptyline prescribed by psychiatrists at 29 medical schools in 9 Asian countries were the same as those used in the United States (Pi et al. 1985). It was also reported that Asians and whites need similar doses of at least 150 mg/day to attain recommended therapeutic blood concentrations (Kinzie et al. 1987). 

Kvist, E.E., A1 Shurbaji, A., Dahl, M.L., Nordin, C., Alvan, G., and Stahle, L. Quantitative pharmacogenetics of nortriptyline A novel approach. Clinical Pharmacokinetics 2001 40 869-877. 

Oshima, N. Kotaki, H. Sawada, Y. Iga, T. Tissue distribution of amitriptyline after repeated administration in rats. Drug Metab.Dispos., 1994,22, 21-25 [rat plasma liver kidney lung brain muscle heart extracted nortriptyline clomipramine is IS column temp 35 LOQ 10 n mL pharmacokinetics]... 

Terlinden, R. Borbe, H.O. Determination of amitriptylinoxide and its major metabolites amitriptyline and nortriptyline in plasma by high-performance liquid chromatography. J.Chromatogr., 1986, 382, 372-376 [plasma column temp 45 extracted amitriptylinoxide desipramine (IS) LOQ 10 ng/mL pharmacokinetics dog]... 

Amitriptyline is rapidly absorbed from the Gl tract and from parenteral sites. Its pharmacokinetics are shown in Table 21.9. Amitriptyline and its active metabolite, nortriptyline, are distributed into breast milk. Amitriptyline is primarily (65%) metabolized by N-demethylation by CYP2D6 to nortriptyline and hydroxylation to its -10-hydroxy metabolite. Nortriptyline is pharmacologically active as a secondary amine TCA. Amitriptyline shows approximately equal affinity for 5-HT and NE transporters. 

Alexanderson B (1972). Pharmacokinetics of nortriptyline in man after single and multiple oral doses the predictability of steady-state plasma concentrations from single dose plasma-level data. Eur JClin Pharmacol 4 82. 

Ayesh R, Dawling S, Widdop B, Idle JR, Smith RL. Influence of quinidine on the pharmacokinetics of nortriptyline and desipramine. BrJ Clin Pharmacol (1988) 25,140P-141P. 

The pharmacokinetic interaction with desipramine is established. Although the clinical relevance of the increased levels has not been assessed, the manufacturer recommends caution if duloxetine is given to patients taking desipramine and other similarly metabolised tricyclics, such as nortriptyline, amitriptyline and imipramine. ... 

A number of other reports and studies clearly confirm that marked increases occur in the levels of amitriptyline, " clomipramine, desipramine, " imipramine " and nortriptyline, " accompanied by toxicity, if fluoxetine is added without reducing the dosage of the tricyclic antidepressant. Delirium and seizures have also been described, and a death has been attributed to chronic amitriptyline toxicity caused by fluoxetine. The pharmacokinetics of fluoxetine appear not to be affected by amitriptyline. ... 

Terbinafme markedly increased the AUC of desipramine in a pharmacokinetic study. Case reports describe increases in the serum levels of amitriptyline, desipramine, imipramine and nortriptyline, with associated toxicity, in patients additionally given oral terbinafme. 

Amitriptyline and nortriptyline plasma levels can be increased by sodium valproate and valpromide, but in contrast, an isolated report attributes a paradoxical rise in serum desipramine levels to the withdrawal of valproic acid. Valproate pharmacokinetics may be moderately affected by amitriptyline. Status epilepticus has been attributed to elevated clomipramine levels in a patient taking valproic acid. 

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