Steady-state kinetics of imipramine in patients

Gram, Lars F.; Søndergaard, Ib; Christiansen, Jan; Petersen, Gorm Odden; Bech, Per; Reisby, N; Ibsen, Ilse; Ortmann, J.; Nagy, Ádám; Dencker, S. J.; Jacobsen, O.; Krautwald, O.

doi:10.1007/bf00426573

Cited by 67 publications

(15 citation statements)

References 20 publications

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“…The numbers above the SDs symbolize significant differences in variation between the age groups: 2, p < 0.01 and 3, p < 0.001. with age. In agreement with previous observations, we found that especially serum amitriptyline levels were increased with advancing age (Gram et al, 1977;Nies et al, 1977). There was also a trend towards an increase in serum doxepin concentrations with ageing, although in agreement with the results ofNorman et al (1979), the total concentration of doxepin + nordoxepin showed no significant increase.…”

Section: Discussionsupporting

confidence: 94%

The influence of ageing on serum levels of tertiary tricyclic antidepressants

Leìnonen

Ylitalo

1991

Human Psychopharmacology

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The influence of ageing on serum levels of tertiary tricyclic antidepressants (TCAs) was studied in 385 psychiatric inpatients treated daily with one of three TCAs: 157 patients with amitriptyline (154 f 47 mg, mean dose +SD), 183 with doxepin (177 f 59 mg) and 45 with clomipramine (153 f 51 mg). The patients were divided into three age groups: 125 of them were aged <35 years, 218 were 35-65 years and 42 were >65 years. The numbers of blood samples for gas-chromatographic monitoring of steady-state concentrations of serum tertiary and secondary TCAs were 192 for amitriptyline, 240 for doxepin and 138 for clomipramine. The concentrations of serum amitriptyline and nortriptyline rose in an age-related manner. The serum clomipramine and norclomipramine concentrations were higher in the middle-aged than in the young patient groups, whereas serum doxepin and nordoxepin concentrations changed less markedly with advancing age. The variations of serum amitriptyline and nortriptyline concentrations were not greater in old patients than in middle-aged ones. Neither were the variations in doxepin and nordoxepin concentrations enlarged with advancing age (but those in clomipramine and norclomipramine concentrations were wider in middle-aged than in young patients). The number of too high ('toxic') TCA concentrations was inconsistently greater in the elderly than in the two younger age groups. The results suggest that the liability of old patients to the adverse effects of TCAs is not-at least with all TCA treatments-due to the enlarged variation in serum drug levels or to the increased frequency of 'toxic' serum TCA concentrations.

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Section: Discussionsupporting

confidence: 94%

The influence of ageing on serum levels of tertiary tricyclic antidepressants

Leìnonen

Ylitalo

1991

Human Psychopharmacology

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“…Humans ordinarily take drugs by swallowing a pill, which introduces a bolus of drug into circulation at that time. Although plasma levels of antidepressant drugs reach a relatively steady level during chronic administration of antidepressant drugs (e.g., Gram et al 1977;Nies et al 1977;Van Brunt 1983), the taking of a pill, or any other form of bolus introduction of drug, will nevertheless cause an increase in blood level shortly after the drug is taken/administered (e.g., Preskorn 1989;Grant and Weiss 2001). In contrast, delivery of drug by minipump produces no variation in blood level resulting from introduction of a bolus of drug.…”

Section: Discussionmentioning

confidence: 99%

A selective test for antidepressant treatments using rats bred for stress-induced reduction of motor activity in the swim test

West

Weiss

2005

Psychopharmacology

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“…and 2-hydroxy-desipramine. Aliphatic hydroxylation It was suggested nearly 20 years ago, that the Nto 10-hydroxy-imipramine and 10-hydroxy-desi-demethylation of imipramine and the 2-hydroxylation pramine, N-oxidation to imipramine-N-oxide and side of imipramine and desipramine are catalyzed by difchain dealkylation to iminodibenzyl are considered ferent P450 isoforms [3,4]. Indeed, subsequent in vivo less important pathways [1].…”

Section: Introductionmentioning

confidence: 99%

Imipramine metabolism in relation to the sparteine and mephenytoin oxidation polymorphisms—a population study.

Madsen¹,

Nielsen²,

Brøsen³

1995

Brit J Clinical Pharma

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1 Sparteine and mephenytoin phenotyping tests were carried out in 327 healthy Danish subjects. Two weeks later each subject took 25 mg imipramine followed by urine collection for 24 h. The urinary content of imipramine, desipramine, 2-hydroxy-imipramine and 2-hydroxy-desipramine was assayed by h.p.l.c. 2 The medians of the hydroxylation ratios (i.e. 2-hydroxy-metabolite over parent compound) were 6 to 14 times higher in 300 extensive metabolizers of sparteine (EMS) as compared with 27 poor metabolizers (PMJ), but none of the ratios separated the two phenotypes completely. 3 There were 324 EM of mephenytoin (EMM) and three PM (PMM) in the sample.The demethylation ratios between desipramine, 2-hydroxy-desipramine and their corresponding tertiary amines showed statistically significant correlations with the mephenytoin S/R isomer ratio (Spearman's rs: -0.20 and -0.27, P < 0.05).4 The demethylation ratios were higher in 80 smokers than in 245 non-smokers. This indicates that CYP1A2, which is induced by cigarette smoking, also catalyzes the N-demethylation of imipramine. 5 CYP2D6 genotyping was carried out by PCR in 325 of the subjects, and the D6-wt allele was amplified in 298 EMS, meaning that they were genotyped correctly. One PM, was D6-wt/D6-B, another PMS had the genotype D6-wt/ and hence both were misclassified as EMS. The remaining 25 PMs were D6-AID6-B (n = 5), D6-B/ (n = 18) or D6-D/D6-D (no PCR amplification, n = 2). Thus, the specificity for genotyping PMs was 100% and the sensitivity was 92.4%. 6 There were 198 apparently homozygous EMS (D6-wt/) and 98 heterozygous EMS (D6-wt/D6-A or D6-wt/D6-B). The sparteine metabolic ratio was lower and the hydroxylation ratios were higher in the homozygotes compared with the heterozygotes. However, for all of the ratios there was a considerable overlap between the two genotypes.

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Steady-state kinetics of imipramine in patients

Cited by 67 publications

References 20 publications

The influence of ageing on serum levels of tertiary tricyclic antidepressants

The influence of ageing on serum levels of tertiary tricyclic antidepressants

A selective test for antidepressant treatments using rats bred for stress-induced reduction of motor activity in the swim test

Imipramine metabolism in relation to the sparteine and mephenytoin oxidation polymorphisms—a population study.

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