Spectral Studies on the Interaction of Imipramine and some of its Oxidized Metabolites with Rat Liver Microsomes

C, von Bahr; Orrenius, Sten

doi:10.3109/00498257109044380

Cited by 40 publications

(5 citation statements)

References 10 publications

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“…These findings suggest that both reactions are catalyzed by different varieties of cytochrome P-450. This suggestion was supported by the fact that in the earlier studies only phenolic hydroxylation was observed (Bickel and Baggiolini 1966;von Bahr and Orrenius 1971;Nakazawa 1970;Perel et al 1974). All these experiments were carried out with microsomes of male rats, whereas in the present study microsomes of female rats were used.…”

Section: Discussionsupporting

confidence: 71%

Comparison of the metabolism of the three antidepressants amitriptyline, imipramine, and chlorimipramine in vitro in rat liver microsomes

Krüger¹,

Hölzl²,

Kuss³

et al. 1986

Psychopharmacology

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The metabolism of the tricyclic antidepressants amitriptyline (AMI), imipramine (IMI), chlorimipramine (CMI) and some of their metabolites was studied in vitro in isolated liver microsomes of female Spraque-Dawley rats. Nine metabolites of AMI, seven metabolites of IMI, and 11 metabolites of CMI were quantitatively determined with high-performance liquid chromatography. The main metabolic reactions, mediated by an NADPH generating system, were hydroxylation, demethylation, and N-oxidation. The ratio of these reactions was different for the three drugs. AMI was hydroxylated more than CMI and CMI more than IMI. The order for demethylation was CMI greater than AMI = IMI, the order for N-oxidation IMI greater than CMI less than or equal to AMI. The substrate dependence of metabolism was investigated. Demethylation and N-oxidation increased proportionally to increasing substrate concentrations, whereas formation of hydroxylated metabolites became saturated (in the concentration range of 10(-6)-10(-5) M). The in vitro metabolism was compared with the in vivo metabolism in humans, reflected by the plasma concentrations of these drugs and their metabolites. A good agreement in metabolic pathways was found.

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Section: Discussionsupporting

confidence: 71%

Comparison of the metabolism of the three antidepressants amitriptyline, imipramine, and chlorimipramine in vitro in rat liver microsomes

Krüger¹,

Hölzl²,

Kuss³

et al. 1986

Psychopharmacology

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“…Blood samples (10 ml) were taken into heparinized Vacutainers 0.5, 1.0, 1. 5,2,3,4,6,8,11,15, and 24 hr after dosing. An additional blood sample was taken at 32 hr after the 100-mg dose (both oral and rectal).…”

Section: Methodsmentioning

confidence: 99%

“…Some other drugs that are subject to extensive metabolic conversion in man during the first circulation through the liver, e.g., alprenolol 4 and nortriptyline,l have a very high affinity to cytochrome P-450 of liver cells. 5,6,9 Binding to this enzyme fraction is thought to be the initial step in oxidative drug metabolic reactions. The affinity of indomethacin to cytochrome P-450 is considerably less as judged from studies of differential spectra.…”

Section: Steady-state Concentration On Four 4-hr Determinationsmentioning

confidence: 99%

Pharmacokinetics of indomethacin

Alván

Orme

Bertilsson

et al. 1975

Clin Pharma and Therapeutics

229

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Plasma concentrations of indomethacin have been studied in 5 healthy volunteers after single and multiple doses (25 mg intravenously [iv], 25, 50, and 100 mg orally, 100 mg rectally, and 25 mg three times daily [tid]. In 8 other normal subjects and in 5 patients a 50-mg oral dose of indomethacin was given and the indomethacin concentration was followed from 8 to 32 hr after dosing. All analyses were carried out using a new mass fragmentographic method. After oral and rectal doses the plasma decay of indomethacin was biphasic, and the data were interpreted according to a 2-compartment open model. The half-life of the beta-phase varied between 2.6 and 11.2 hr. The volume of distribution ranged from 0.34 to 1.57 L/kg and the plasma clearance from 0.044 to 0.109 L/kg/hr. There was no evidence of dose-dependent elimination. Indomethacin was rapidly and well absorbed after oral dosing with peak plasma concentrations within 2 hr. Comparison with the area under the curve (AUC) after iv dosing indicated complete bioavailability. The AUC after rectal dosing indicated complete bioavailability, but the rate of absorption was slower than after oral administration. Indomethacin, 25 mg three times daily, was also given for 9 days to the same normal subjects; equilibrium concentrations obtained did not differ significantly (p greater than 0.1) from those predicted from single-dose data in the 5 subjects.

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“…The competition is however not seen often. Apart from the competition of phenytoin and p-HPPH, there are desmethylimipramine, imipramine, 25 phenylbutazone, 26 antipyrine, 27 sulfisoxazole, orphenadrine, 30 and 7,12-dimethylbenz[u]nthracene. 31 The product inhibition of 7,12-dimethylbenz[u]nthracene that occurs specifically on cytochrome P-45Oc was reported.…”

Section: Inhibition Of P-hpph Formation By P-hpphmentioning

confidence: 99%

Stereoselective inhibition of diphenylhydantoin metabolism by p‐hydroxyphenyl‐phenylhydantoin enantiomers in rats

Huang

Hsieh

1991

Chirality

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Different doses of rac-p-HPPH (0.4 and 4 mg/h) were given repeatedly to rats infused with [14C]phenytoin. The serum levels of 14C-labeled and unlabeled p-HPPH, and [14C]phenytoin were measured by an HPLC method and radiometric analysis. The clearance of phenytoin and p-HPPH was determined by rate of dosing divided by the steady-state concentration. The phenytoin clearance was significantly lower in the high dose p-HPPH injection group than in the low dose group (87 versus 262 ml/h), whereas p-HPPH clearance showed no difference. The formation clearance of [14C]p-HPPH was also significantly lower in rats injected with high dose of p-HPPH (35 versus 169 ml/h). The clearance of other elimination pathways was also lower in rats with high dose of p-HPPH (53 versus 89 ml/h). The serum protein binding of phenytoin was lower in rats injected with high dose of p-HPPH. The result indicated that injections of rac-p-HPPH mainly inhibited on the formation of p-HPPH itself. The formation of (R)-p-HPPH and (S)-p-HPPH in microsomal preparation was measured by a ligand-exchange chromatographic method. The formation of (S)-p-HPPH or (R)-p-HPPH was not only inhibited by the enantiomer itself, but also cross-inhibited by the other enantiomer. To the formation of either (S)-p-HPPH or (R)-p-HPPH, (S)-p-HPPH showed a higher inhibitory activity. The use of rac-p-HPPH to inhibit phenytoin metabolism in vivo involved several mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

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Spectral Studies on the Interaction of Imipramine and some of its Oxidized Metabolites with Rat Liver Microsomes

Cited by 40 publications

References 10 publications

Comparison of the metabolism of the three antidepressants amitriptyline, imipramine, and chlorimipramine in vitro in rat liver microsomes

Comparison of the metabolism of the three antidepressants amitriptyline, imipramine, and chlorimipramine in vitro in rat liver microsomes

Pharmacokinetics of indomethacin

Stereoselective inhibition of diphenylhydantoin metabolism by p‐hydroxyphenyl‐phenylhydantoin enantiomers in rats

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