Pharmacokinetics Of Nortriptyline Research Articles

Effects of Genetic Polymorphism in CYP2D6, CYP2C19, and the Organic Cation Transporter OCT1 on Amitriptyline Pharmacokinetics in Healthy Volunteers and Depressive Disorder Patients.

The tricyclic antidepressant amitriptyline is frequently prescribed but its use is limited by its narrow therapeutic range and large variation in pharmacokinetics. Apart from interindividual differences in the activity of the metabolising enzymes cytochrome P450 (CYP) 2D6 and 2C19, genetic polymorphism of the hepatic influx transporter organic cation transporter 1 (OCT1) could be contributing to interindividual variation in pharmacokinetics. Here, the impact of OCT1 genetic variation on the pharmacokinetics of amitriptyline and its active metabolite nortriptyline was studied in vitro as well as in healthy volunteers and in depressive disorder patients. Amitriptyline and nortriptyline were found to inhibit OCT1 in recombinant cells with IC50 values of 28.6 and 40.4 µM. Thirty other antidepressant and neuroleptic drugs were also found to be moderate to strong OCT1 inhibitors with IC50 values in the micromolar range. However, in 35 healthy volunteers, preselected for their OCT1 genotypes, who received a single dose of 25 mg amitriptyline, no significant effects on amitriptyline and nortriptyline pharmacokinetics could be attributed to OCT1 genetic polymorphism. In contrast, the strong impact of the CYP2D6 genotype on amitriptyline and nortriptyline pharmacokinetics and of the CYP2C19 genotype on nortriptyline was confirmed. In addition, acylcarnitine derivatives were measured as endogenous biomarkers for OCT1 activity. The mean plasma concentrations of isobutyrylcarnitine and 2-methylbutyrylcarnitine were higher in participants with two active OCT1 alleles compared to those with zero OCT1 activity, further supporting their role as endogenous in vivo biomarkers for OCT1 activity. A moderate reduction in plasma isobutyrylcarnitine concentrations occurred at the time points at which amitriptyline plasma concentrations were the highest. In a second, independent study sample of 50 patients who underwent amitriptyline therapy of 75 mg twice daily, a significant trend of increasing amitriptyline plasma concentrations with decreasing OCT1 activity was observed (p = 0.018), while nortriptyline plasma concentrations were unaffected by the OCT1 genotype. Altogether, this comprehensive study showed that OCT1 activity does not appear to be a major factor determining amitriptyline and nortriptyline pharmacokinetics and that hepatic uptake occurs mainly through other mechanisms.

Quantitative Modeling Analysis Demonstrates the Impact of CYP2C19 and CYP2D6 Genetic Polymorphisms on the Pharmacokinetics of Amitriptyline and Its Metabolite, Nortriptyline.

Amitriptyline is a tricyclic antidepressant that is metabolized mainly by CYP2C19 and CYP2D6 enzymes. Higher plasma levels of amitriptyline and its active metabolite, nortriptyline, are associated with an increased risk of adverse events including anticholinergic effects. The aim of this study was to evaluate the effects of CYP2C19 and CYP2D6 genetic polymorphisms on amitriptyline and nortriptyline pharmacokinetics. Twenty-four Korean healthy adult male volunteers were enrolled in the study after stratification by their CYP2C19 and CYP2D6 genotypes. Serial blood draws for pharmacokinetic analysis were made after a single oral 25-mg dose of amitriptyline was administered. Plasma amitriptyline and nortriptyline concentrations were measured by a validated liquid chromatography with tandem mass spectrometry. Population pharmacokinetic modeling analysis was conducted using NONMEM, which evaluated the effects of CYP2C19 and CYP2D6 genotypes on amitriptyline and nortriptyline pharmacokinetics. The biotransformation of amitriptyline into nortriptyline was significantly different between subjects with the CYP2C19*2/*2, *2/*3, and *3/*3 genotypes and those with the other genotypes, with an estimated metabolic clearance of 17 and 61.5 L/h, respectively. Clearance of amitriptyline through pathways other than biotransformation into nortriptyline was estimated as 18.8 and 30.6 L/h for subjects with the CYP2D6*10/*10 and *10/*5 genotypes and those with the other genotypes, respectively. This study demonstrated a quantitative effect of the CYP2C19 and CYP2D6 genotypes on amitriptyline and nortriptyline pharmacokinetics. Production of nortriptyline from amitriptyline was associated with CYP2C19 genotypes, and clearance of amitriptyline through pathways other than biotransformation into nortriptyline was associated with CYP2D6 genotypes. These observations may be useful in developing individualized, optimal therapy with amitriptyline.

Influence of ABCB1 (P‐glycoprotein) haplotypes on nortriptyline pharmacokinetics and nortriptyline‐induced postural hypotension in healthy volunteers

A single nucleotide polymorphism in ABCB1, which encodes P-glycoprotein, has retrospectively been associated with symptoms of nortriptyline-induced postural hypotension in depressed patients. This finding needs to be replicated in independent studies before recommendations regarding pharmacogenetic testing can be made. In a prospective study of healthy volunteers homozygous for ABCB1 (1236-2677-3435, TTT/TTT or CGC/CGC), a single dose of nortriptyline was administered, plasma exposure was determined and blood pressure and heart rate were monitored during posture change. No differences between ABCB1 haplotype groups were found in plasma exposure of nortriptyline and its active metabolites, E- and Z-10-hydroxynortriptyline. The heart rate response to posture change was increased with nortriptyline, whereas there was no difference in blood pressure response. However, no differences between haplotype groups were observed except that the pre dose heart rate response to standing was greater in the TTT than CGC homozygotes. The association between ABCB1 polymorphisms and nortriptyline-induced postural hypotension found in a previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline. AIMS To investigate the influence of ABCB1 (1236-2677-3435) polymorphisms on nortriptyline pharmacokinetics and nortriptyline-induced postural hypotension in healthy volunteers. Genetic screening of 67 healthy volunteers identified eight CGC homozygotes and nine TTT homozygotes of ABCB1 (1236-2677-3435), who were administered a single dose of nortriptyline 25 mg. Plasma exposure of nortriptyline and its active metabolites, E- and Z-10-hydroxynortriptyline, was determined over 72 h. Heart rate and blood pressure responses to posture change (active standing and passive head-up tilt) were measured continuously using finger plethysmography. There were no differences in plasma exposure between ABCB1 haplotype groups, as the geometric mean (95% CI) AUC(0,72 h) ratios were 0.98 (0.94, 1.03), 1.02 (0.96, 1.09) and 0.95 (0.80, 1.10) for nortriptyline, E- and Z-10-hydroxynortriptyline, respectively. The pre dose heart rate response to standing was greater in the TTT than CGC homozygotes (mean (95% CI) difference 7.4 (1.5, 13.4) beats min(-1) , P = 0.02). At t(max) at 8 h post dose, nortriptyline increased the heart rate response to posture change in all subjects with mean (95% CI) Δ heart rate values of 7.4 (3.6, 11.3) beats min(-1) on active standing (P = 0.0009) and 4.8 (2.0, 7.6) beats min(-1) on head-up tilt (P = 0.002), but no difference was observed between haplotype groups. There was no difference in blood pressure response to posture change in either group. The association between ABCB1 polymorphisms and nortriptyline-induced postural hypotension found in the previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline.

Risk assessment of accidental nortriptyline poisoning: The importance of cytochrome P450 for nortriptyline elimination investigated using a population-based pharmacokinetic simulator

It is not possible to make a prospective clinical study that reveals the importance of the nortriptyline metabolising cytochrome P450 (CYP) isoforms (CYP1A2, CYP2C19, CYP2D6, and CYP3A4) in relation to attaining potential toxic nortriptyline concentrations with a possibly fatal outcome. Therefore to study this we have applied the population based pharmacokinetic simulator Simcyp. The objective was to estimate how important CYP2C19 and CYP2D6 phenotype status, hepatic activity of CYP3A4, body weight, CYP2D6 phenotype dose adjustment, and drug–drug interactions are with regard to accidental poisoning in a virtual population receiving a daily dose of 100 mg nortriptyline. Accidental poisoning is here defined as intake of a normal dose which because of slow metabolism may lead to potentially toxic concentrations. The input parameters values for Simcyp were based on average literature in vitro and in vivo data. The Simcyp simulations of nortriptyline pharmacokinetics reflected reported clinical concentration–time profiles, therapeutic drug monitoring data, and the consequence of CYP2D6 poor metaboliser (PM) and ultrarapid metaboliser status. Of the investigated factors, the simulations indicate that having CYP2D6 PM status is a major risk factor for attaining high concentrations and thereby possibly becoming poisoned by nortriptyline. Of the CYP2D6 PM subjects 16% would attain plasma concentrations exceeding the toxic limit. Individuals with the combination of CYP2D6 PM status and 10% of the average liver CYP3A4 expression had a 90% risk of becoming poisoned. The results point towards the combination of low CYP3A4 activity and CYP2D6 PM status of major importance for attaining possibly toxic nortriptyline concentrations. In a forensic toxicological context, the results indicate that both the activity of CYP3A4, information on possible drug–drug interactions, and the genotype of CYP2D6 are needed in order to elucidate whether an individual might have been accidentally poisoned because of slow metabolism. In a clinical context, the simulations suggest that precise individual dose adjustment of nortriptyline requires information regarding the activity of both CYP3A4 and CYP2D6. This underlines the value of therapeutic drug monitoring for nortriptyline. Population based pharmacokinetic simulations are considered useful tools for risk assessment in clinical and forensic toxicology.

P.2.093 The early diagnose of the psychiatric side effects of interferon-alpha

It is not possible to make a prospective clinical study that reveals the importance of the nortriptyline metabolising cytochrome P450 (CYP) isoforms (CYP1A2, CYP2C19, CYP2D6, and CYP3A4) in relation to attaining potential toxic nortriptyline concentrations with a possibly fatal outcome. Therefore to study this we have applied the population based pharmacokinetic simulator Simcyp. The objective was to estimate how important CYP2C19 and CYP2D6 phenotype status, hepatic activity of CYP3A4, body weight, CYP2D6 phenotype dose adjustment, and drug–drug interactions are with regard to accidental poisoning in a virtual population receiving a daily dose of 100 mg nortriptyline. Accidental poisoning is here defined as intake of a normal dose which because of slow metabolism may lead to potentially toxic concentrations. The input parameters values for Simcyp were based on average literature in vitro and in vivo data. The Simcyp simulations of nortriptyline pharmacokinetics reflected reported clinical concentration–time profiles, therapeutic drug monitoring data, and the consequence of CYP2D6 poor metaboliser (PM) and ultrarapid metaboliser status. Of the investigated factors, the simulations indicate that having CYP2D6 PM status is a major risk factor for attaining high concentrations and thereby possibly becoming poisoned by nortriptyline. Of the CYP2D6 PM subjects 16% would attain plasma concentrations exceeding the toxic limit. Individuals with the combination of CYP2D6 PM status and 10% of the average liver CYP3A4 expression had a 90% risk of becoming poisoned. The results point towards the combination of low CYP3A4 activity and CYP2D6 PM status of major importance for attaining possibly toxic nortriptyline concentrations. In a forensic toxicological context, the results indicate that both the activity of CYP3A4, information on possible drug–drug interactions, and the genotype of CYP2D6 are needed in order to elucidate whether an individual might have been accidentally poisoned because of slow metabolism. In a clinical context, the simulations suggest that precise individual dose adjustment of nortriptyline requires information regarding the activity of both CYP3A4 and CYP2D6. This underlines the value of therapeutic drug monitoring for nortriptyline. Population based pharmacokinetic simulations are considered useful tools for risk assessment in clinical and forensic toxicology.

Pathogenetic role of cyclooxygenase‐2 in hyperprostaglandin E syndrome/antenatal bartter syndrome: Therapeutic use of the cyclooxygenase‐2 inhibitor nimesulide

Patients with hyperprostaglandin E syndrome/antenatal Bartter syndrome typically have renal salt wasting, hypercalciuria with nephrocalcinosis, and secondary hyperaldosteronism. Antenatally, these patients have fetal polyuria, leading to polyhydramnios and premature birth. Hyperprostaglandin E syndrome/antenatal Bartter syndrome is accompanied by a pathologically elevated synthesis of prostaglandin E(2), thought to be responsible for aggravation of clinical symptoms such as salt and water loss, vomiting, diarrhea, and failure to thrive. In this study administration of the cyclooxygenase-2 (COX-2) specific inhibitor nimesulide to patients with hyperprostaglandin E syndrome/antenatal Bartter syndrome blocked renal prostaglandin E(2) formation and relieved the key parameters hyperprostaglandinuria, secondary hyperaldosteronism, and hypercalciuria. Partial suppression of serum thromboxane B(2) synthesis resulting from platelet COX-1 activity and complete inhibition of urinary 6-keto-prostaglandin F(1alpha), reflecting endothelial COX-2 activity, indicate preferential inhibition of COX-2 by nimesulide. Amelioration of the clinical symptoms by use of nimesulide indicates that COX-2 may play an important pathogenetic role in hyperprostaglandin E syndrome/antenatal Bartter syndrome. Moreover, on the basis of our data we postulate that COX-2-derived prostaglandin E(2) is an important mediator for stimulation of the renin-angiotensin-aldosterone system in the kidney.

Inhibition of cytochrome P4502D6 activity with paroxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline pharmacokinetics and the debrisoquin test

Inhibition of cytochrome P4502D6 activity with paroxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline pharmacokinetics and the debrisoquin test

Pharmacokinetics of nortriptyline and its 10-hydroxy metabolite in Chinese subjects of different CYP2D6 genotypes.

To study the impact of the CYP2D6*10 allele on the disposition of nortriptyline in Chinese subjects. A single dose of 25 mg nortriptyline was given orally to 15 healthy Chinese volunteers who were classified as extensive metabolizers after phenotyping with debrisoquin (INN, debrisoquine) and who were genotyped by allele-specific polymerase chain reaction. Five subjects were homozygous for CYP2D6*1, 5 subjects were homozygous for CYP2D6*10, and 5 subjects were heterozygous for these 2 alleles. Plasma concentrations of nortriptyline and its main metabolite 10-hydroxynortriptyline were measured by liquid chromatography-mass spectrometry, and the pharmacokinetics were studied during 168 hours after the dose. Subjects who were homozygous for CYP2D6*10 had significantly higher total areas under the plasma concentration-time curve (AUC), lower apparent oral clearances, and longer mean plasma half-life of nortriptyline than subjects in the CYP2D6*1/*1 and the heterozygous groups. For 10-hydroxynortriptyline, the AUC was lower and the plasma half-life was longer in subjects who were homozygous for CYP2D6*10 than in subjects in the other 2 groups. The CYP2D6*10 allele in Chinese subjects was associated with significantly higher plasma levels of nortriptyline compared with the CYP2D6*1 allele because of an impaired metabolism of nortriptyline to 10-hydroxynortriptyline, particularly in the subjects with the CYP2D6*10/*10 genotype. The results suggest that genotyping of CYP2D6 may be a useful tool in predicting the pharmacokinetics of nortriptyline.

10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes.

To investigate the disposition and effects of nortriptyline and its major metabolite 10-hydroxy-nortriptyline line in panels of white subjects with different CYP2D6 genotypes, including those with duplicated and multiduplicated CYP2D6*2 genes and to evaluate the contribution of the number of functional C gamma P2D6 alleles to the metabolism of nortriptyline, used here as a model drug for CYP2D6 substrates. Oral single doses of 25 to 50 mg nortriptyline were given to five poor metabolizers of debrisoquin (INN; debrisoquine) with no functional CYP2D6 gene, five extensive metabolizers with one functional CY2D6 gene, five extensive metabolizers with two functional CYP2D6 genes, five ultrarapid metabolizers with duplicated CYP2D6*2 genes, and one ultrarapid metabolizer with 13 copies of the CYP2D6*2 gene. Plasma kinetics of nortriptyline and 10-hydroxynortriptyline were analyzed. Anticholinergic effects (inhibition of salivation and accommodation disturbances), sedation, blood pressure, and effect on supine and erect pulse rate were measured. There was a clear relation between the C gamma P2D6 genotype and the plasma kinetics of nortriptyline and 10-hydroxynortriptyline. The proportion between the apparent oral clearances of nortriptyline in the groups with 0, 1, 2, 3, and 13 functional genes was 1:1:4:5:17. The proportions between AUC(nortriptyline) to AUC(10-hydroxynortriptyline) ratios in the groups with 0, 1, 2, 3, and 13 functional genes were 36:25:10:4:1. Oral plasma clearance of nortriptyline and AUC(nortriptyline) to AUC(10-hydroxynortriptyline) ratio both correlated significantly with the debrisoquin metabolic ratio (rS = -0.89, p = 0.0001; rS = 0.92, p = 0.0001). Although ultrarapid metabolizer subjects were given double the nortriptyline dose (50 mg), inhibition of salivation was not more pronounced compared with the other genotype groups given 25 mg nortriptyline. The results of this study show the quantitative importance of the CYP2D6 genotype, especially the presence of multiple functional CYP2D6 genes for the pharmacokinetics of nortriptyline and 10-hydroxynortriptyline. Genotyping of subjects with multiple copies of functional genes may be of great value for differentiating ultrarapid metabolizers from patients who do not comply with the prescription and for assuring adequate drug choice and dosage for these patients.

Effects of divalproex sodium on amitriptyline and nortriptyline pharmacokinetics.

Divalproex sodium has been found to be efficacious in the prophylaxis of migraine headaches and the management of the manic phase of bipolar syndrome. Because amitriptyline is also prescribed in these patient populations, data are needed on their potential for interaction. The effect of concomitant administration of divalproex sodium on the pharmacokinetics of amitriptyline and its active metabolite, nortriptyline, was investigated in an open-label, sequential, two-period phase I study. Ten healthy male and five healthy female subjects received 50 mg amitriptyline hydrochloride on two occasions: (1) alone (period 1) and (2) 2 hours after receiving the ninth dose of 500 mg divalproex sodium (Depakote) administered once every 12 hours (period 2). Amitriptyline area under the curve was increased 31% from the combined effect of decreased first-pass metabolism and inhibition of systemic metabolism. The elevated nortriptyline plasma levels reflected primarily the increase in amitriptyline concentrations but also appeared to involve modest inhibition of nortriptyline elimination. For the sum of amitriptyline and nortriptyline concentrations, the peak plasma concentration mean was 19% higher with concomitant divalproex dosing. The mean area under the curve for the sum of amitriptyline and nortriptyline concentrations was 42% higher with concomitant divalproex dosing than it was for dosing with amitriptyline alone. These results suggested that a lower dose of amitriptyline might be considered when divalproex is administered concomitantly.

Population pharmacokinetics of nortriptyline during monotherapy and during concomitant treatment with drugs that inhibit CYP2D6‐an evaluation with the nonparametric maximum likelihood method.

Therapeutic drug monitoring data for nortriptyline (674 analyses from 578 patients) were evaluated with the nonparametric maximum likelihood (NPML) method in order to determine the population kinetic parameters of this drug and their relation to age, body weight and duration of treatment. Clearance of nortriptyline during monotherapy exhibited a large interindividual variability and a skewed distribution. A small, separate fraction with a very high clearance, constituting between 0.5% and 2% of the population, was seen in both men and women. This may be explained by the recent discovery of subjects with multiple copies of the gene encoding the cytochrome-P450-enzyme CYP2D6, which catalyses the hydroxylation of nortriptyline. However, erratic compliance with the prescription may also add to this finding. A separate distribution of low clearance values with a frequency corresponding to that of poor metabolizers of CYP2D6 (circa 7% in Caucasian populations) could not be detected. Concomitant therapy with drugs that inhibit CYP2D6 resulted in a major increase in the plasma nortriptyline concentrations. This was caused by a decrease in nortriptyline clearance, whereas the volume of distribution was unchanged. The demographic factors age and body weight had a minor influence on the clearance of nortriptyline which was also unaffected by the duration of treatment.

Steady state pharmacokinetics of nortriptyline in the frail elderly.

The frail elderly, for whom chronic disease and disability are essentially universal, are at high risk for depression and are specifically vulnerable to the adverse effects of antidepressant medication. There have, however, been few investigations of either the pharmacokinetics or the clinical investigations of either the pharmacokinetics or the clinical response to antidepressants in such patients. We report on the pharmacokinetics of nortriptyline at steady state in a group of 22 patients, average age 84, living within an institutional setting. Comparison of our findings with those previously reported for younger and healthier subjects suggests that there are no clinically significant group differences in nortriptyline kinetics. Plasma levels of nortriptyline and those of both the trans- and cishydroxylated metabolites are linear with daily dose. Mean (and SD) for the parameter (plasma level/dose) was 1.21 (0.63) ng/ml/mg/day for the parent compound, 1.41 (0.86) for the trans metabolite, and 0.30 (0.16) for the cis metabolite. There was no significant correlation across individuals between the accumulation of the parent compound and the metabolites. Based upon these data, the average dose of nortriptyline required to achieve a plasma level of 100 ng/ml is 80 mg/day. Dose requirements, however, vary between individuals by a factor of 20. Plasma levels measured 24 hours after a 25-mg test dose of nortriptyline can allow early identification of slow metabolizers. Twenty-four-hour plasma levels (mean 8.8 ng/ml, SD 3.2) were significantly correlated with steady state levels at 25 mg/day (r = 0.71), steady state levels at 50 mg/day (r = 0.73), and each individual's average (plasma level/dose) (r = 0.57).

Nortriptyline Pharmacokinetic Parameters in Depressed Children and Adolescents

The pharmacokinetic parameters of nortriptyline in the pediatric age group following oral administration of a single dose of 25 or 50 mg were investigated from nortriptyline plasma level assays at 12, 18, 24, 36, and 48 hours postdose. Data were analyzed separately for the nine prepubertal and 11 postpubertal subjects, all of whom were diagnosed major depressive disorder. These data were compared with studies in the literature of nortriptyline pharmacokinetics from adult and geriatric normal and depressed populations. Similar to adults, the elimination of nortriptyline in children and adolescents is apparently first order kinetics with a logarithmically linear rate of disappearance. The prepubertals had a shorter mean half-life (17.6 +/- 3.7 hours) than some adult groups and twice a day dosage would, therefore, be more appropriate for many children. Although the mean half-life (27.1 +/- 17.1 hours) for the adolescent group suggested that once a day dosage would be sufficient, some adolescents would need twice a day dosage for optimum plasma level control because there was a wide range (14.1 to 76.2 hours). The almost twofold variation in half-life in prepubertals and fivefold variation in postpubertals were similar to differences in adult groups and emphasize the value of plasma level monitoring in the clinical use of nortriptyline.

The pharmacokinetics of nortriptyline in patients with chronic renal failure.

1 The pharmacokinetics of single oral doses of nortriptyline were studied in twenty patients with chronic renal failure, eight of whom were receiving treatment with haemodialysis. 2 The median nortriptyline half-life was 25.2 h (range 14.5-140.0 h) and the median nortriptyline clearance was 32.3 l/h (range 8.1-122.0 l/h). 3 No differences were observed between the dialysed and non-dialysed groups. 4 Comparisons of nortriptyline half-life and clearance between the patients and groups of physically healthy subjects revealed no significant differences. 5 There was no significant linear correlation between age and either of these measurements. In the twelve patients not receiving haemodialysis there was no correlation between nortriptyline clearance and glomerular filtration rate. 6 Chronic renal failure is not associated with a significant alteration in nortriptyline metabolism as measured by its half-life or clearance, but the drug should nonetheless be used with caution, and monitored whenever possible. However, the marked inter-individual differences observed in nortriptyline half-life and clearance in patients with chronic renal failure may not be solely responsible for their unpredictable response to tricyclic antidepressant therapy, and other possible contributory factors are discussed.

Pharmacokinetics of nortriptyline in elderly depressed patients and prediction of optimal dosage regimes [proceedings

British Journal of Clinical PharmacologyVolume 9, Issue 3 p. 306P-307P Free Access Pharmacokinetics of nortriptyline in elderly depressed patients and prediction of optimal dosage regimes [proceedings] RA Braithwaite, RA BraithwaiteSearch for more papers by this authorP Crome, P CromeSearch for more papers by this authorS Dawling, S DawlingSearch for more papers by this authorRR Lewis, RR LewisSearch for more papers by this author RA Braithwaite, RA BraithwaiteSearch for more papers by this authorP Crome, P CromeSearch for more papers by this authorS Dawling, S DawlingSearch for more papers by this authorRR Lewis, RR LewisSearch for more papers by this author First published: March 1980 https://doi.org/10.1111/j.1365-2125.1980.tb04863.xCitations: 1AboutPDF 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 Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume9, Issue3March 1980Pages 306P-307P ReferencesRelatedInformation

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

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

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.

Studies on the metabolism and pharmacokinetics of nortriptyline and desmethylimipramine in man

Studies on the metabolism and pharmacokinetics of nortriptyline and desmethylimipramine in man