Nortriptyline In Man Research Articles

Stereoselective reversible ketone formation from 10-hydroxylated nortriptyline metabolites in human liver.

1. E- and Z-10-hydroxynortriptyline are major metabolites of amitriptyline and nortriptyline in man. Upon incubation with human liver microsomes or cytosol, these metabolites were oxidized to the corresponding ketones, E- and Z-10-oxonortriptyline. (+)-E- and (+)-Z-10-hydroxynortriptyline were distinctly preferred over the (-)-isomers as substrates. NADP+ supported the oxidation in cytosol, whereas in microsomes NAD+ was the best cofactor. 2. Incubation of E- and Z-10-oxonortriptyline with NADPH and cytosol resulted in the nearly exclusive formation of (+)-E- and (+)-Z-10-hydroxynortriptyline. Kinetic analysis revealed high-affinity reduction (K(m) 1-2 microM) of the two ketones and an additional low-affinity component with the E-isomer. 10-Oxonortriptyline reduction was also catalysed by rabbit, but not by rat or guinea pig liver cytosol. 3. With [4-3H]NADPH as cosubstrate, tritium was incorporated into E- and Z-10-hydroxynortriptyline preferentially from the pro-4R position. Redox cycling of (+)-E- and (+)-Z-10-hydroxynortriptyline in cytosol in the presence of NAD- and NADPH was indicated by 3H incorporation from [pro-4R-3H]NADPH. 4. Recombinant human carbonyl reductase catalysed low-affinity reduction of E-10-oxonortriptyline with preferential transfer of the pro-4S-3H of labelled NADPH. 5. Ketone reduction in cytosol was strongly inhibited by 9,10-phenanthrenequinone and dehydrolithocholic acid and moderately by other 3-oxo steroids and some anti-inflammatory drugs. 6. The high-affinity reduction of E- and Z-10-oxonortriptyline and the oxidation of the alcohols in cytosol are probably mediated by a member of the aldo-keto reductase family of enzymes.

The debrisoquine hydroxylation test predicts steady-state plasma levels of desipramine.

British Journal of Clinical PharmacologyVolume 15, Issue 3 p. 388-390 Free Access The debrisoquine hydroxylation test predicts steady-state plasma levels of desipramine. L Bertilsson, L BertilssonSearch for more papers by this authorA Aberg-Wistedt, A Aberg-WistedtSearch for more papers by this author L Bertilsson, L BertilssonSearch for more papers by this authorA Aberg-Wistedt, A Aberg-WistedtSearch for more papers by this author First published: March 1983 https://doi.org/10.1111/j.1365-2125.1983.tb01518.xCitations: 66AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL References ABERG-WISTEDT, A. (1982). A double-blind study of zimelidine, a serotonin uptake inhibitor, and desipramine, a noradrenaline uptake inhibitor in endogenous depression. I. Clinical findings. Acta Psychiat. Scand., 66, 50– 65. ALEXANDERSON, B. (1972). Pharmacokinetics of desmethylimpramine and nortriptyline in man after single and multiple oral doses—A cross-over study. Eur. J. clin. Pharmac., 5, 1– 10. ALEXANDERSON, B. (1973). Prediction of steady-state plasma levels of nortriptyline from single oral dose kinetics: A study in twins. Eur. J. clin. Pharmac., 6, 44– 53. BERTILSSON, L., DENGLER, H.J., EICHELBAUM, M. & SCHULZ, H.-U. (1980). Pharmacogenetic covariation of defective N-oxidation of sparteine and 4-hydroxylation of debrisoquine. Eur. J. clin. Pharmac., 17, 153– 155. HAMMER, W. & SJOQVIST, F. (1967). Plasma levels of monomethylated tricyclic antidepressants during treatment with imipramine-like compounds. Life Sci., 6, 1895– 1903. HAMMER, W., MARTENS, S. & SJÖQVIST, F. (1969). A comparative study of the metabolism of desmethylimi-pramine, nortriptyline and oxyphenylbutazone in man. Clin. Pharmac. Ther., 10, 44– 49. MAHGOUB, A., IDLE, J.R., DRING, L.G., LANCASTER, R. & SMITH, R.L. (1977). Polymorphic hydroxylation of debrisoquine in man. Lancet, ii, 584– 586. MELLSTRÖM, B., BERTILSSON, L., SÄWE, J., SCHULZ, H.-U. & SJOQVIST, F. (1981). E- and Z-10-hydroxylation of nortriptyline: Relationship to polymorphic debrisoquine hydroxylation. Clin. Pharmac. Ther., 30, 189– 193. POTTER, W.Z., BERTILSSON, L. & SJÖQVIST, F. (1981). Clinical pharmacokinetics of psychotropic drugs: Fundamental and practical aspects. In Handbook of Biological Psychiatry, VI, eds H. Praag, M.H. Lader, O.J. Rafaelsen & E.J. Sachar, pp 71– 134. New York: Marcel Dekker Inc. POTTER, W.Z., CALIL, H.M., SUTFIN, T.A., ZAVADIL, A.P., JUSKO, W.J., RAPOPORT, J. & GOODWIN, F.K. (1982). Active metabolites of imipramine and desipramine in man. Clin. Pharmac. Ther., 31, 393– 401. Citing Literature Volume15, Issue3March 1983Pages 388-390 ReferencesRelatedInformation

251) - Pharmacokinetics of nortriptyline in man: Its circadian effect

251) - Pharmacokinetics of nortriptyline in man: Its circadian effect

First-pass metabolism of nortriptyline in man.

The kinetics of nortriptyline were studied after oral and intravenous (iv) administration of test doses of 50 mg 14C-nortriptyline. The systemic availability of orally administered nortriptyline varied from 0.46 to 0.59 in 6 subjects. The decrease in availability was due to metabolism after administration. Systemic clearance varied from 0.31 to 0.66 L/min. From these measurements indirect estimates of the hepatic blood flow could be made, and a variation from 0.6 to 1.5 L/min was found. Quantitative measurements of first-pass metabolism could also be obtained from urinary metabolite excretion data when the kinetics of metabolite formation and elimination were taken into account. From the second or third day after the test dose, the urinary excretion rate of total radioactivity declined monoexponentially with half-lives closely corresponding to the plasma half-lives of unchanged nortriptyline. Analysis of the data from the iv test according to a 2-compartment open model showed that there was a close correlation between the rate constant of distribution from central to peripheral compartment (k12) and the elimination rate constant in the central compartment (kel). Still, there was some variation in the kel/k12-ratio, and this variation corresponded to the variation of the estimated hepatic blood flow.

Kinetics of nortriptyline in man according to a two compartment model

Plasma concentrations of nortriptyline have been assayed in four subjects after intravenous infusion of 57 mg nortriptyline hydrochloride. The data were evaluated according to a two compartment open model. The calculated best-fitting curves were in good agreement with the experimental data, better than could be expected from a simpler model. This justifies the assumption that the kinetics of nortriptyline in man may be described by this model with an appropriate input function. The data permitted estimation of all the parameters of the model. The meaning of the parameters is discussed, particularly in relation to individual variation.

Pharmacokinetics of desmethylimipramine and nortriptyline in man after single and multiple oral doses ? A cross-over study

Eight healthy volunteers received single oral doses (1 mg/kg) and 6 received multiple doses (0.4 mg/kg t.i.d. for 2 weeks) of desmethylimipramine (DMI) and nortriptyline (NT) on different occasions. Kinetic analysis of plasma levels of the drugs showed that the ratios between single-dose peak-levels, plasma half-lives and apparent mean “steady-state” plasma levels of the two drugs were constant in all the subjects, and averaged 0.6. Despite their closely related chemical structures the apparent plasma clearance rate of DMI was about twice that of NT, and this might be associated with their different degrees of binding to plasma proteins. — The “steady-state” plasma level of NT in man is known to be genetically determined, and the conformity within each individual of the plasma clearance rates of DMI and NT indicates that the plasma kinetics of both these drugs are controlled by common genetic factors. — The study also shows that the “steady-state” plasma level of DMI, like that of NT, can be predicted accurately from single-dose plasma-level data. Thus, if the kinetic characteristics of one of these drugs in a subject are known, it is possible to predict the plasma kinetics of the other compound.

Stereospecific hydroxylation of nortriptyline in man in relation to interindividual differences in its steady-state plasma level

Thecis andtrans isomers of 10-hydroxynortriptyline (10-OH-NT), the major metabolite of nortriptyline (NT) in man, have been separated and quantitated in urine from 6 healthy volunteers who received NT orally, 0.4 mg/kg body weight, three times daily. The isomers were separated by preparative thin layer chromatography and quantitatively determined by gas chromatography as the 10,11-dehydronortriptyline heptafluorobutyryl derivative. The structure of these derivatives producedin vitro was confirmed by gas chromatography — mass spectrometry. Less than 1% of totally excreted 10-OH-NT was accounted for as 10,11-dehydronortriptyline. — Despite interindividual differences in the mean steady-state plasma concentration of NT, the ratio between the two isomers was constant in all subjects (1:4–5). The isomers were both optically active and circular dichroism spectra showed that the asymmetric carbon atoms in the two compounds have different configurations. — It is concluded that NT undergoes stereospecific hydroxylation in man and that there is no correlation between the mean steady-state plasma concentration of NT and the proportion of thecis andtrans isomers formed.

Interindividual differences in plasma protein binding of nortriptyline in man ? A twin study

The binding ratio,rA, of plasma proteins for nortriptyline (NT), a tricyclic antidepressant drug, was investigated by a plasma-plasma equilibrium dialysis technique at 4°C in 7 identical and 10 fraternal sets of twins. The mean steady-state plasma concentrations of NT during oral administration of NT (0.2 mg per kg body weight, t.i.d. for 8 days) were known for all subjects from a previous study. — A two-fold variation inrA was found (from 0.86 to 1.55), and there were significant intrapair differences inrA, both in identical (P<0.01) and fraternal pairs (P<0.0005). The variance ofrA between individuals within pairs was significantly greater in dizygotic than in monozygotic twinships (P<0.025). — It is concluded that plasma protein binding of NT is influenced both by environmental and genetic factors. The interindividual differences in NT-binding to plasma proteins could not be correlated with variations in its steady-state plasma concentrations.

Pharmacokinetics of nortriptyline in man after single and multiple oral doses: the predictability of steady-state plasma concentrations from single-dose plasma-level data.

Six healthy volunteers were given nortriptyline (NT) in single (1 mg/kg) and multiple (0.4 mg/kg) oral doses with the purpose to study the pharmacokinetics of NT in plasma. The single-dose plasma levels in 3 subjects were applied to a two-compartment open model (Model II) which might be suitable for the disposition kinetics of NT. There were significant (P<0.0005) interindividual differences in the observed mean steady-state plasma concentration,C-0304;, of NT which ranged from 51.7 to 111.0 ng/ml.C-0304; was better correlated to the single-dose plasma clearance rate of NT (r=0.98;P<0.0005) than to the single-dose plasma half-life, (t 1/2)β, (r=0.89;P<0.05). Thus the steady-state plasma level can be accurately predicted from single-dose studies. The apparent volume of distribution of NT at pseudodistribution equilibrium, (Vd)β, varied between 21.1 and 31.1 lit./kg body weight assuming complete absorption of the administered dose. There was no significant correlation (r=0.56) between the single-dose and post steady-state plasma half-lives of NT within individuals. NT does not seem to affect its own metabolismin vivo in man since the single- and multiple-dose plasma clearance rates of the drug were similar within subjects. It is concluded that there might be interindividual differences in both the apparent elimination rate and in the distribution of NT. This may be of importance in the pharmacogenetics of NT.

Pharmacokinetics and biological effects of nortriptyline in man.

Pharmacokinetics and biological effects of nortriptyline in man.

Excretion of Nortriptyline Hydrochloride in Man I: Detection and Determination of Urinary Nortriptyline

A quantitative U.V. spectrophotometric assay procedure has been developed for the determination of urinary nortriptyline in man. A thin-layer chromatographic system is described which allows rapid detection of the presence of the drug and its metabolites in urine. The drug was found to be slowly eliminated as a mixture of free drug and metabolites.