Multiple-Dose Pharmacokinetics of Imipramine and Its Major Active and Conjugated Metabolites in Depressed Patients

Sutfin, T A; Perini, Giulia; Molnár, George; Jusko, William J.

doi:10.1097/00004714-198802000-00009

Cited by 26 publications

(14 citation statements)

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“…Thus, a complex picture emerges regarding the molecular activities occurring over the time course of drug and metabolite exposures as well as among different individuals (Caccia and Garattini, 1990). Following administration of imipramine, it can be estimated that the norephinephrine transporter is almost completely occupied by desipramine (free plasma concentration/IC 50 ratio of 20) (Borga et al, 1969;Sutfin et al, 1988;SzymuraOleksiak et al, 2001). 2-Hydroxydesipramine concentrations are approximately half of those of the parent and is approximately 3-fold more potent at the norepeinephrine transporter than imipramine suggesting that it also can contribute more to the occupancy of that protein (Javaid et al, 1979;Nelson et al, 1983).…”

mentioning

confidence: 99%

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Obach

2013

Pharmacol Rev

137

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mentioning

confidence: 99%

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Obach

2013

Pharmacol Rev

137

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“…12, NO. 4 HDCG/HDC = 2.61), which is 50% less than the results from Bock et al (1982), Nielsen et al (1992), and Suftin et al (1988).…”

Section: Plasma Concentrations Of Hcg and Hdcgmentioning

confidence: 60%

“…However, Bock et al reported an about fourfold interindividual variation of GR in 27 patients receiving amitriptyline (Bock et al 1982), and Suftin et al (1988) reported an approximately 13-fold interindividual variation in GR in 14 subjects receiving 200 mg of imipramine for 7 days. Interindividual variation in GR observed in this study seems to be larger than those of previous reports (Bock et al 1982;Suftin et al 1988), and this might be due to the difference in sample size between previous reports and ours.…”

Section: Interindividual Variation Of Glucuronidation Of Hydroxylatedmentioning

confidence: 99%

“…These findings are consistent with the report of Nielsen et al (1992); however, it is contradictory to the fact that the quarternary ammonium-linked glucuronide of amitriptyline has been found in urine from patients receiving therapeutic doses of amitriptyline, which suggests direct conjugation of the parent compound, amitriptyline (Dahl-Puustinen et al 1987Lehman et al 1983). Nielsen et al (1992) reported that incubation of samples from Caucasian subjects who were treated with clomipramine hydrochloride with B-glucuronidase/ arylsulfatase increased the plasma concentrations of HC and HDC by average factors of about 7 and 3, respectively, while Suftin et al (1988) reported that appreciable glucuronide conjugate accumulation was observed in patients treated with 200 mg/day of imipramine hydrochloride with average serum concentration ratios of 8.1 and 6.2 for 2-hydroxyimipramine glucuronide/2-hydroxyimipramine and 2-hydroxydesipramine glucuronide/2-hydroxydesipramine, respectively. Bock et al (1982) reported an average serum concentration ratio ( = 2-hydroxydesipramine glucuronide/2-hydroxydesipramine) of approximately 12 in plasma from subjects treated with 2.5 mg/kg/day of desipramine, while Bock et al (1983) and Lieberman et al (1985) reported average ratio [ = (unconjugated 10-hydroxyamitriptyline + unconjugated 10-hydroxynortriptyline)/(10-hydroxyamitriptyline glucuronide + 10-hydroxynortriptyline glucuronide) of about 4 and 1, respectively.…”

Section: Plasma Concentrations Of Hcg and Hdcgmentioning

confidence: 99%

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Metabolism of Clomipramine in a Japanese Psychiatric Population: Hydroxylation, Desmethylation, and Glucuronidation

Saito

Noguchi²,

Ozeki

et al. 1995

Neuropsychopharmacology

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We measured the concentrations of clomipramine and its metabolites, Tricyclic antidepressants: Clomipramine; Hydroxylation; Desmethylation; Glucuronidation Interindividual differences in drug metabolism, which determine plasma levels or adverse drug effects, have been observed. In particular, the existence of poor metabolizers has been noted for various drugs, including debrisoquine, sparteine, mephenytoin, or desipramine (Jacqz et al. 1986). For example, plasma levels of TCAs varied considerably between individuals treated even with similar doses of the same drug, which suggests that such pharmacokinetic variation reflected interindividual differences in drug metabolism (Hammer and Sjoqvist 1967). Alexanderson et al. (1969) also investigated steady-state plasma levels of nortriptyline in monozygotic and dizygotic twins, concluding that variability in steady-state plasma concentrations between individuals was mostly genetically determined.Clomipramine (C), a chlorinated analog of imipramine, has become one of the most frequently used TCAs since 1960s for the treatment of psychiatric illness. Clomipramine has been reported to be a potent inhibitor of serotonin reuptake, and its active desmethylated and/or hydroxylated metabolites inhibit the reuptake of both serotonin and/or noradrenaline.Despite the widespread use of C, relatively little is known about its metabolism and phamacokinetics in humans. By analogy with the metabolism of imipramine, the major route of biotransformation of C is des-0893-133X/95/$9 .50 SSDI 0893-133X(94)00098-K

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“…Treatment with imipramine leads to accumulation of glucuronides of 2-hydroxyimipramine and 2-hydroxydesipramine (Sutfin et al 1988). Treatment with imipramine leads to accumulation of glucuronides of 2-hydroxyimipramine and 2-hydroxydesipramine (Sutfin et al 1988).…”

Section: Glucuronidation In Health and Diseasementioning

confidence: 99%

Glucuronidation of Drugs

Kroemer

Klotz

1992

Clinical Pharmacokinetics

135

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Glucuronides of drugs are considered to be generally inactive and rapidly eliminated. Therefore, these metabolites are often not taken into account in evaluating drug effects. The present review describes examples of both direct and indirect contributions of glucuronides to net drug effects. Multiple lines of evidence indicate that morphine-6-glucuronide has analgesic activity. This compound has a high affinity to the mu-receptor, is capable of penetrating the blood/brain barrier and is a potent analgesic after administration to patients. Indirect activity of glucuronides may consist of a systemic cycle in which an active parent compound is derived from the glucuronide by enzymatic action. Such systemic cycling has been demonstrated for clofibric acid. In addition, some acyl glucuronides are subject to intramolecular rearrangement and the resulting metabolites are resistant to beta-glucuronidase. Covalent protein binding of glucuronides by different mechanisms may contribute to drug toxicity and immune responses. If glucuronides are accepted as potential modifiers of net drug action it is important to determine what factors modulate disposition of these compounds. Therefore, the later section of this review describes glucuronidation under different pathophysiological conditions. Examples for alterations of the rate and/or extent of glucuronidation by concurrent diseases processes, age and coadministration of other drugs are provided.

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Multiple-Dose Pharmacokinetics of Imipramine and Its Major Active and Conjugated Metabolites in Depressed Patients

Cited by 26 publications

References 0 publications

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Metabolism of Clomipramine in a Japanese Psychiatric Population: Hydroxylation, Desmethylation, and Glucuronidation

Glucuronidation of Drugs

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