Glucuronidation clearance of 8-hydroxyclomipramine in relation to sparteine and mephenytoin phenotype

Nielsen, Kristina Tomra; Brøsen, Kim; Gram, Lars F.; Hansen, M. G. J.

doi:10.1007/bf00194975

Cited by 4 publications

(3 citation statements)

References 7 publications

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“…, 1998). Clomipramine and DCMP are mainly metabolized by hydroxylation in the aromatic positions 2 and 8 by CYP2D6 and the hydroxylated metabolites are rapidly glucuronidated and excreted in the urine (Faigle & Dieterle, 1973; Nielsen et al. , 1994; Wu et al.…”

Section: Introductionmentioning

confidence: 99%

“…The main route is N-demethylation to the active metabolite, desmethylclomipramine (DCMP) catalyzed by CYP3A4, CYP2C19, CYP2C9 and CYP1A2 (Kruger et al, 1986;Nielsen et al, 1996;Wu et al, 1998). Clomipramine and DCMP are mainly metabolized by hydroxylation in the aromatic positions 2 and 8 by CYP2D6 and the hydroxylated metabolites are rapidly glucuronidated and excreted in the urine (Faigle & Dieterle, 1973;Nielsen et al, 1994;Wu et al, 1998). DCMP may be further demethylated to didesmethylclomipramine (DiDCMP) (Nielsen et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Comparative oxidative metabolic profiles of clomipramine in cats, rats and dogs: preliminary results from an in vitro study

Lainesse¹,

Frank

Beaudry³

et al. 2007

Vet Pharm & Therapeutics

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The objectives of this in vitro study were to describe cytochrome-dependent metabolism of clomipramine in canine and feline microsomes, compare metabolic profiles between cats, rats and dogs, and investigate a potential gender-related difference in metabolic activity between male and female cats. Pooled liver microsomes were incubated with clomipramine, where species and gender-specific reactions were initiated by the addition of a nicotinamide adenine dinucleotide phosphate regenerating system and quenched with methanol at 0, 5, 15, 30, 45 and 60 min, and 0, 30, 60, 90, 120, 180, 240 and 360 min respectively. Liquid chromatography tandem mass spectrometry was used to measure clomipramine and its metabolites. Preliminary results showed that cat microsomes biotransformed clomipramine slower and less efficiently than rat and dog microsomes. Moreover, gender differences in metabolic profiles suggested that male cat microsomes may be less efficient demethylators and hydroxylators than female cat microsomes. As gender metabolic differences may carry clinical significance for this antidepressant, further studies are warranted.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparative oxidative metabolic profiles of clomipramine in cats, rats and dogs: preliminary results from an in vitro study

Lainesse¹,

Frank

Beaudry³

et al. 2007

Vet Pharm & Therapeutics

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“…In patient studies carried out by the Danish University Antidepressant Group (DUAG), 150 mg/day clomipramine has shown a strong antidepressant efficacy that clearly surpasses that of the new antidepressants citalopram, paroxetine, and moclobemide 16 , 17 , 18 . The clinical pharmacokinetics of clomipramine have been well studied, including identification of major metabolites, steady‐state kinetics, and the role of genetic polymorphisms 19 , 20 , 21 , 22 , 23 . Earlier studies on concentration‐effect relationships of clomipramine have suggested a linear relationship, but generally the correlations were weak 24 , 25 , 26 , 27 .…”

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confidence: 99%

Clomipramine dose-effect study in patients with depression: Clinical end points and pharmacokinetics

1999

Clinical Pharmacology & Therapeutics

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Objective To examine the problems of establishing dose‐effect and concentration‐effect relationships of antidepressant therapy with clomipramine. Methods This randomized double‐blind study compared five fixed doses of clomipramine hydrochloride: 25, 50, 75, 125, and 200 mg/day in hospitalized or day patients at nine clinical centers in Denmark. A 1‐week washout period was followed by 6 weeks of active treatment and weekly depression ratings. In total, 151 patients (100 women and 51 men) with major depression scoring ≥18 on the Hamilton Depression Scale (HDS) or ≥9 on the Hamilton Depression subscale (HDSS) before and after the washout period were randomized. The treatment groups (n = 29 to 32) were well balanced with respect to sex, age, and depression rating. Serum concentrations of clomipramine plus metabolites were measured at weekly intervals. A sparteine test was performed before and during drug treatment. Results There was pronounced interpatient variability in response and kinetics at each dose. Drop‐outs attributable to adverse events increased with rising doses, whereas drop‐outs caused by worsening or lack of effect or nonresponse declined with increasing dose. Completer analyses showed a moderate and statistically significant relationship between depression rating and dose at all ratings after 1 to 6 weeks of treatment (trend analysis). HDS items representing core symptoms of depression showed a particularly consistent dose‐effect relationship. Early sustained response occurred more frequently with the two highest doses. Serum levels of clomipramine and desmethylclomipramine showed weak correlation with depression ratings (R s = −0.18 to −0.27; P < .05 to P < .01). A few blood pressure measurements and a few typical side‐effect ratings showed a statistically significant dose‐effect and concentration‐effect relationship. Serum concentration of clomipramine and desmethylclomipramine showed a pronounced disproportionate increase with increasing dose. Clomipramine inhibited in a dose‐dependent fashion CYP2D6 (sparteine oxidation). Conclusion The dose‐effect curves, indicating the probability of a certain outcome at a given dose, were flat and overlapping suggesting a narrow therapeutic range. This pattern is similar to that observed with newer antidepressants. Clinical Pharmacology & Therapeutics (1999) 66, 152–165; doi:

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Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects

Poulsen

Brøsen

Arendt‐Nielsen

et al. 1996

European Journal of Clinical Pharmacology

212

128

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This study confirms that codeine O-demethylation depends on CYP2D6; it shows that the 6-glucuronidation of morphine is independent of CYP2D6; it supports the theory that the analgesic effect of codeine depends on its O-demethylation; and it indicates that this is probably also the case for the adverse effects. The results lend no support to the suggestion of a non-opioid analgesic effect of codeine.

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Glucuronidation clearance of 8-hydroxyclomipramine in relation to sparteine and mephenytoin phenotype

Cited by 4 publications

References 7 publications

Comparative oxidative metabolic profiles of clomipramine in cats, rats and dogs: preliminary results from an in vitro study

Comparative oxidative metabolic profiles of clomipramine in cats, rats and dogs: preliminary results from an in vitro study

Clomipramine dose-effect study in patients with depression: Clinical end points and pharmacokinetics

Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects

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