First‐pass metabolism of nortriptyline in man

Gram, Lars F.; Overø, K. Fredricson

doi:10.1002/cpt1975183305

Cited by 79 publications

(13 citation statements)

References 10 publications

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“…2 However, the calculation also assumes complete availability to the central compartment of the absorbed dose (F* = I), which would not be true if DOX were extensively metabolized during its first pass through the liver, as has been demonstrated for imipramine 16 and nortriptyline. 17 If there were such a first-pass metabolism, the calculated values of V d and CLp would be falsely elevated. Assuming a liver blood flow of 1,500 ml/min, the fraction of the absorbed dose reaching the systemic circulation (F*) was estimated.…”

Section: Resultsmentioning

confidence: 98%

Doxepin kinetics

Ziegler

Biggs

Wylie

et al. 1978

Clin Pharma and Therapeutics

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The kinetics of doxepin (DOX) hydrochloride were studied in 7 volunteers after the oral administration of 75 mg. Peak plasma concentrations of DOX ranged from 8.8 to 45.8 ng/ml and were reached within 4 hr. The disappearance of DOX was biphasic and followed first-order kinetics. The mean DOX half life (t1/2) was 16.8 hr and in individuals ranged from 8.2 to 24.5 hr. The mean apparent volume of distribution was 20.2 L/kg and ranged from 9.1 to 33.3 L/kg. The estimated first-pass metabolism of DOX ranged from 55% to 87% of the oral dose assuming complete absorption. Significant quantities of the metabolite desmethyldoxepin (DMD) were produced. Peak levels of DMD ranged from 4.8 to 14.5 ng/ml and were reached between 2 and 10 hr after administration. The mean t1/2 of DMD was 51.3 hr and in individuals ranged from 33.2 to 80.7 hr. There was no correlation between the DOX and DMD t1/2s. The amount of DMD produced correlated with the plasma concentration of DOX and appears to explain the correlation between the steady-state concentrations of DOX and DMD in patients given DOX.

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Section: Resultsmentioning

confidence: 98%

Doxepin kinetics

Ziegler

Biggs

Wylie

et al. 1978

Clin Pharma and Therapeutics

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“…This is characteristic for some tricyclic antidepressants in man, as well. The percentage of doxepin metabolized on the first-pass has been estimated as 55-87% (14), that of nortriptyline as 34-48% (15,16,17), that of imipramine as 53% (18), and that of protriptyline as 10-25% (19). Further pharmacokinetic studies are needed to clarify the significance of the first-pass effect of nomifensine in man.…”

Section: Resultsmentioning

confidence: 99%

First-pass metabolism of nomifensine in dogs

Lindberg

Sellman²,

Iisalo

1985

European Journal of Drug Metabolism and Pharmacokinetics

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Nomifensine (1 and 5 mg/kg) was administered to dogs orally and intravenously. The pharmacokinetics of the drug was evaluated. Nomifensine was rapidly absorbed from the gastro-intestinal tract reaching maximum concentration at 0.5-1 h. The peak levels were directly proportional to the doses administered. The elimination half-life was 6 h and only very small amounts were found in blood at 24 h after administration. The apparent volume of distribution (Vd) was 120-149 1, suggesting an extensive distribution of the drug throughout body fluids and tissues. The area under the serum concentration-time curve (AUC) obtained after oral administration was significantly smaller than that after intravenous administration indicating incomplete bioavailability of the drug in oral form. The conjugation of nomifensine after the two different administration routes was also studied: the conjugation reaction was in equilibrium at 15 min after oral administration, while after intravenous administration, equilibrium was not reached until 1-1.5 h. The metabolism of nomifensine occurred in the gastrointestinal membranes and or in the liver during the absorption process; the first-pass effect was marked.

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“…To investigate this phenomenon more thoroughly, an age and sex matching technique was used. The studies of volunteers (Alexanderson, 1972b(Alexanderson, , 1973Gram & Over0, 1975; were searched preferentially for a partner of the same sex and similar age (within the same decade) as for each of the patients with chronic renal failure. Eleven partners were found from these sources.…”

Section: Discussionmentioning

confidence: 99%

The pharmacokinetics of nortriptyline in patients with chronic renal failure.

Dawlilng¹,

Lynn²,

Rosser³

et al. 1981

Brit J Clinical Pharma

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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.

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First‐pass metabolism of nortriptyline in man

Cited by 79 publications

References 10 publications

Doxepin kinetics

Doxepin kinetics

First-pass metabolism of nomifensine in dogs

The pharmacokinetics of nortriptyline in patients with chronic renal failure.

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