Imipramine metabolism in man

Christiansen, J.; Gram, Lars F.; Kofod, B.; Rafaelsen, Ole J.

doi:10.1007/bf00405231

Cited by 38 publications

(4 citation statements)

References 10 publications

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“…Slow urinary excretion has also been observed in other studies. 5 Some of the radioactivity might have been eliminated by the bile and feces. 6 The rate of elimination of systemically distributed IP will be determined by its distribution as well as the metabolic capacity of the liver.…”

Section: Discussionmentioning

confidence: 99%

“…This was done by extraction and 2-dimensional thin-layer chromatography according to methods described previously. 5,12 In this study dichlormethane was used for extraction in order to simplify the extraction procedure and increase the recovery; 50% to 70% of the radioactivity in the extracts was recovered on the thin-layer chromatogram. About two thirds of the radioactivity represented known metabolites, and about one third was found in other spots representing unidentified metabolites.…”

Section: Methodsmentioning

confidence: 99%

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First‐pass metabolism of imipramine in man

Gram

Christiansen

1975

Clin Pharma and Therapeutics

117

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The systemic availability of orally administered imipramine (IP) varied from 29 to 77% in 4 subjects. The decrease in availability was due to an excess in metabolism after oral administration. This first-pass metabolism did not correlate with plasma half-life, apparent clearance, or the rate of metabolite excretion in urine. There was close correlation with the excess in formation of demethylated metabolites after oral administration, which suggests that the first-pass metabolism is mediated by demethylation, but does not correlate to the total rate of demethylation.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

First‐pass metabolism of imipramine in man

Gram

Christiansen

1975

Clin Pharma and Therapeutics

117

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“…was counted in a Packard liquid scintillation spectrometer according to methods described previousl y. 10,17 14C-NT was labeled in a position a to the N atom in the side chain.…”

Section: Methodsmentioning

confidence: 99%

First‐pass metabolism of nortriptyline in man

Gram

Overø

1975

Clin Pharma and Therapeutics

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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.

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“…Desipramine is rapidly and completely absorbed when taken orally, with peak concentrations occurring 2 to 6 h post‐dose [4]. Distribution is largely determined by the lipophilic nature of desipramine, which distributes widely to various tissues.…”

Section: Introductionmentioning

confidence: 99%

Desipramine, substrate for CYP2D6 activity: population pharmacokinetic model and design elements of drug–drug interaction trials

Gueorguieva¹,

Jackson²,

Wrighton³

et al. 2010

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Desipramine is extensively metabolized by CYP2D6 to its main metabolite 2-OH-desipramine.• Alternative metabolic pathways are 10-hydroxylation and further demethylation to didesipramine, but the concentration of these metabolites in plasma upon therapeutic oral doses are very low both in extensive and poor metabolizers of substrates of CYP2D6. • Desipramine has been used widely as a probe drug for CYP2D6 activity. WHAT THIS STUDY ADDS• The population pharmacokinetics of desipramine in healthy subjects were characterized.• The model allows performing simulations of trials which assess CYP2D6 interaction potential of novel compounds.• Study design elements, such as required sample size based on desipramine within and between-subject variance and optimal sampling schedules for the three subgroups, intermediate, extensive and ultrarapid metabolizers of CYP2D6 are suggested. AIMSTo develop a population pharmacokinetic model to describe the pharmacokinetics of desipramine in healthy subjects, after oral administration of a 50 mg dose. Additional objectives were to develop a semi-mechanistic population pharmacokinetic model for desipramine, which allowed simulation of CYP2D6-mediated inhibition, when using desipramine as a probe substrate, and to evaluate certain study design elements, such as duration of desipramine pharmacokinetic sampling, required sample size and optimal pharmacokinetic sampling schedule for intermediate, extensive and ultrarapid metabolizers of CYP2D6 substrates. RESULTSThe mean population estimates of the first order absorption rate constant (ka), apparent clearance (CL/F) and apparent volume of distribution at steady state (Vss/F) were 0.15 h -1, 111 l h -1 and 2950 l, respectively. Further, using the proposed semi-mechanistic hepatic intrinsic clearance model with Bayesian inference, mean population desipramine hepatic intrinsic clearance was estimated to be 262 l h -1 with between-subject variability of 84%. D-optimal PK sampling times for intermediate metabolizers were calculated to be approximately 0.25, 24, 75 and 200 h. Similar sampling times were found for ultrarapid and extensive metabolizers except that the second D-optimal sample was earlier at 14 and 19 h, respectively, compared with 24 h for intermediate metabolizers. This difference in sampling times between the three genotypes can be attributed to the different intrinsic clearances and elimination rates. CONCLUSIONSA two compartment population pharmacokinetic model best described desipramine disposition. The semi-mechanistic population model developed is suitable to describe the pharmacokinetic behaviour of desipramine for the dose routinely used in drug-drug interaction (DDI) studies. Based on this meta-analysis of seven trials, a sample size of 21 subjects in cross-over design is appropriate for assessing CYP2D6 interaction with novel compounds.

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Imipramine metabolism in man

Cited by 38 publications

References 10 publications

First‐pass metabolism of imipramine in man

First‐pass metabolism of imipramine in man

First‐pass metabolism of nortriptyline in man

Desipramine, substrate for CYP2D6 activity: population pharmacokinetic model and design elements of drug–drug interaction trials

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