Imipramine excretion

At least 20 metabolites of imipramine, excreted in human urine, were identified by two-dimensional TLC. These metabolites resulted from a eexn-bination of mono- or di-demethylation or dealkylation of the side chain and hydroxylation at the 2 or 10 position with subsequent conjugation. Imipramine N-oxide was also detected as well as a new, unidentified conjugating group. 

Metabolism converts a lipophilic molecule into a more hydrophilic (water-loving) metabolite that can be excreted in urine by the kidneys. In the majority of cases the drug is detoxified, or made pharmacologically inactive by this metabolic breakdown. However, a few drugs need to be metabolised to become psychoactive for instance, the sedative-hypnotic chloral hydrate is converted to the active metabolite trichloroethanol. In this case the parent molecule is referred to as a prodrug. With many drugs, both the parent compound and its metabolites are psychoactive. An example of this is the tricyclic antidepressant imipramine which is metabolised to desipramine, with... 

Mehendale HM. 1977b. Effect of preexposure to Kepone on the biliary excretion of imipramine and sulfobromophthalein. Toxicol Appl Pharmacol 40 247-259. 

Mehendale HM. 1977c. Mirex-induced impairment of hepatobiliary function Suppressed biliary excretion of imipramine and sulfobromophthalein. Drug Metab Dispos 5 56-62. 

Pregnancy Category D- amitriptyline, imipramine, nortriptyline Category C -amoxapine, clomipramine, desipramine, doxepin, protriptyline, trimipramine). Lactation These agents are excreted into breast milk in low concentrations. 

Precursor therapy as a means of increasing dopaminergic transmissions is limited to L-tyrosine and L-dopa. Although under basal conditions the exogenous administration of tyrosine leads to specific enhancement of noradrenergic transmission, it can enhance dopaminergic transmission in conditions of DA deficiency [Kapur and Mann 1992). Only one adequately controlled clinical trial has been reported, in which 65 patients with major depression were randomly selected to treatment for 4 weeks with oral L-tyrosine 100 mg/kg/day, imipramine 2.5 mg/kg/day, or placebo [Gelenberg et al. 1990). Tyrosine increased and imipramine decreased excretion of the main metabolite of NA, but no evidence was found that tyrosine had antidepressant activity in contrast with imipramine. 

There are few reports on the excretion of antidepressant drugs in breast milk, even though postpartum depression is relatively common. In a 32-year-old woman who took imipramine 200 mg/day from 1 month postpartum imipra-mine and desipramine were detectable in breast milk... 

Sovner R, Orsulak PJ. Excretion of imipramine and desi-pramine in human breast milk. Am J Psychiatry 1979 136(4A) 451-2. 

The phenothiazines, such as chlorpromazine, used in the treatment of schizophrenia, the tricyclic antidepressant drugs such as imipramine and amitryp-tUine, antimalarials such as quinacrine, and the anticancer agent adriamycin are structural analogs of riboflavin (see Figure 7.6) and inhibit flavokinase. In experimental animals, administration of these drugs at doses equivalent to those used clinically results in an increase in the EGR activation coefficient (Section 7.5.2) and increased urinary excretion of riboflavin, with reduced tissue concentrations of riboflavin phosphate and FAD, despite feeding diets providing more riboflavin than is needed to meet requirements (Pinto et al., 1981). 

There are few reports on the excretion of antidepressant drugs in breast milk, even though postpartum depression is relatively common. In a 32-year-old woman who took imi-pramine 200 mg/day from 1 month postpartum imipramine and desipramine were detectable in breast milk (135). There have also been reports that amitriptyline (136), desipramine (137), and nortriptyline (138,139) were detectable in the milk of nursing mothers and in the plasma of the mothers and infants. Neither parent compound nor metabolite were detected in infants serum, except for two infants who had low concentrations of 10-hydroxynortriptyline. There were no adverse effects in any of the infants. The use of antidepressants during lactation has been reviewed, including 15 studies in which serum concentrations of antidepressants were obtained from nursing infants (140). 

When a dmg is in its unionised form it will more readily diffuse from the urine to the blood. In an acidic urine, acidic drugs will diffuse back into the blood from the urine. Acidic compounds such as nitrofurantoin are excreted faster when the urinary pH is alkaline. Amfetamine, imipramine and amitriptyline are excreted more rapidly in acidic urine. The control of urinary pH in studies of pharmacokinetics is thus vital. It is difficult, however, to find compounds to use by the oral route for deliberate adjustment of urinary pH. Sodium bicarbonate and ammonium chloride may be used but are unpalatable. Intravenous administration of acidifying salt solutions presents one approach, especially for the forced diuresis of basic dmgs in cases of poisoning. 

The demethyluted metabolite is less anticholinergic. Id) sedative, and more stimulatory and is a, SNERI." Cone quently. a patient treated with imipramine has two con pounds that contribute to activity. Overall, the efieci isno selective 5-HT versus NE reuptake. The activity of dcs-- norimipraminc is terminated by 2-hydroxyl,ntion, fnlliwo by conjugation and excretion. A. second N-demcihylaliit... 

It has been shown that some unipolar depressed female patients have high COMT (catechol-O-methyl transferase) activity in their red blood cells, and that this observation correlates with a poor response to imipramine. 24 On the other hand, high COMT activity may correspond to high MHPG excretion. This finding supports the previous disclosure that low MHPG excretors respond to imipramine. 

A 55-year-old patient currently receiving other drugs for another condition is to be started on diuretic therapy for rrald heart failure. Thiazides are known to reduce the excretion of (A) Diazepam Fluoxetine Imipramine Lithium Potassium... 

Imipramine. The urinary excretion ofa test dose of C-imipramine given to two schizophrenie patients was reduced by about 35 to 40% when they took haloperidol 12 to 20 mg daily. The plasma metabolite levels of C-nortriptyline of another schizophrenie fell while taking haloperidol 16 mg daily, whereas plasma levels of unehanged nortriptyline rose. ... 

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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