Imipramine distribution

Tanger, S.Z., Javoy-Agid, E, Raisman, R., Briley, M., and Agid, Y. (1981) Distribution of specific high-affinity binding sites for [3H]imipramine in human brain./ Neurochem 37 267—271. 

It is structurally and chemically related to tricyclic antidepressant drug imipramine and pharmacologically it is similar to diphenyl hydantoin sodium. It is effective in grandmal and psychomotor epilepsy and also in the treatment of trigeminal neuralgia (a condition characterized by paroxysms of intense pain of stabbing nature within the area of distribution of trigeminal nerve without sensory loss). 

Absorption and distribution The TCAs are well absorbed upon oral administration, and because of their lipophilic nature, are widely distributed and readily penetrate into the CNS. This lipid solubility also causes these drugs to have long half-lives, for example, 4 to 17 hours for imipramine. As a result of their variable first pass metabolism in the liver, TCAs have low and inconsistent bioavailability. Therefore the patient s response is... 

Tricyclics (TCAs) TricycUc antidepressant drugs (eg, imipramine, amitriptyline) are stmcturally related to the phenothiazine antipsychotics and share certain of their pharmacologic effects. The tricycUcs are weU-absorbed orally but may undergo first-pass metabolism. They have high volumes of distribution and are not readily dialyzable. Exten-... 

Desipramine is a dihydrodibenzazepine secondary amine TCA that also is the active metabolite of imipramine (Fig. 21.8). Desipramine appears to have a bioavailability comparable to the other secondary TCAs (Table 21.3). Desipramine is distributed into milk in concentrations similar to those present at steady state in maternal plasma. This drug is metabolized primarily by CYP2D6 to its 2-hydroxy metabolite and by CYP1A2 and CYP2C19 to its N-demethylated (primary amine) metabolite (Table 21.2). 

Lofepramine differs from imipramine by the attachment of a p-chlorophenacyl moiety to the N-aminopropyl side chain (Fig. 21.17). This change confers enhanced lipophilicity and the potential of more rapid distribution into the CNS with greater in vitro affinity and selectivity for NET. Its mechanism of antidepressant action is attributed to its rapid metabolism to the secondary amine metabolite, desipramine, which selectively inhibits the neuronal uptake of NE (66). 

A detailed study of the absorption and distribution of imipramine and the formation of 1 metabolites was reported. In contrast to an earlier report, data were presented which confirmed that desipramine is the pharmacologically active metabolite of imipramine55i5o. Urinary excretion of 3 methoxy-4-hydroxyphenylglycol (MHPG), the major metabolite of NE in brain57, was significantly lowered in depressed patients58. 

Pharmacokinetic constants for the absorption and elimination of pralid-oxime have been determined in man83. a pharmacokinetic model for flow, lipid solubility, protein binding and saturation-IImited metabolism of thiopental has permitted the a priori prediction of bodily distribution conslsten with experiment . Imipramine and its metabolites are rapidly distributed in the rat and renally and biliary excreted with enterohepatic circulation . Mathematical models have been established for the pharmacokinetics of neurohypophysial and related peptides . The oral administration of 2,3,5, triiodebenzoic acid in goats and a cow by whole-body radioactivity retention showed a rapid distributive and subsequent exponential elimination phase with the metabolites formed by deiodination . Bishydroxycoumarin shows dose-dependent first order elimination in man but not in other species and has been assigned to dose effects on el imi nation . ... 

Antidepressive activity was noted for some tricyclic compounds having a six-membered central ring. A series of naphthyrldones, C-29 C-42 ( ). and C- 5 (7c). caused inlpramine—like activity in animals. The Influence of on central biogenic amine levels," as well as its absorption, distribution and excretion, was Investigated in mice and rats. Several phenothiazine derivatives had antidepressive activity. In extensive clinical trials fluoracizine (8a). a CPj analog of chloracizine, showed antidepressive efficacy equivalent to imipramine. 

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