Drug metabolism chlorpromazine

Rabbit strains may exhibit up to 20-fold variation, particularly in the case of hexobarbital, amphetamine, and aminopyrine metabolism. Relatively smaller differences between strains occur with chlorpromazine metabolism. Wild rabbits and California rabbits display the greatest differences from other rabbit strains in hepatic drug metabolism. 

SCHEME 11.28 Cimetidine is an example of a drug metabolized by FM03-catalyzed S-oxidation other FM03 substrates include chlorpromazine, also a CYP3A substrate. 

Suzuki Y, Someya T, Shimoda K, Hirokane G, Morita S, Yok io A, Inoue Y, Takaha S. Importance of thie cytochrone P450 2D6 geno lT>e for the drug metabolic interaction between chlorpromazine and haloperidol. Ther Drug Mornt( ) 23,363-8. 

Often a single drug will have many metabolites including some which have effects similar to the parent (cyclosporin, chlorpromazine). Microsomal drug metabolism can be stimulated by medications such as the barbiturate phenobarbital or by cigarette smoke. Metabolism may be slowed by medications such as the monoamine oxidase inhibitors which are used in treatment of psychiatric disease. There are genetic and sex-related differences as well as age-related effects which may affect an individual patient s metabolism. 

In addition to drugs administered specifically to produce a metabolic effect, there are drug-related physiological changes that cause laboratory test abnormalities. Many drugs have been associated with the appearance of abnormal liver function tests in a fashion that simulates extrahepatic obstruction. These drugs include, among others, chlorpromazine, cinco-phen, methyltestosterone, thiouracil, p-aminosalicylic acid, sulfadiazine, reserpine, meprobromate, novobiocin, caffeine, and phenacemide (L7, L8, S6). 

Chlorpromazine was the first, and probably is still the most widely used, major tranquilizer. Although 95-98 of the drug in plasma is bound to protein, it is extensively and rapidly metabolized within the body into a large number of metabolites. Much of the metabolism may indeed take place in the gut before, or in the gut mucosa during absorption. 

Chlorpromazine is 92 to 97% bound to plasma proteins, principally albumin [5,20], It crosses the blood-brain barrier, and concentrations of the drug in the brain are higher than those in plasma [17], The relationship of plasma concentration to clinical response and toxicity has not been clearly established. Chlorpromazine and its metabolites cross the placenta and are distributed into milk [21]. About 10-12 metabolites of chlorpromazine in humans have been identified. In addition to hydroxylation at positions 3 and 7 of the phenothiazine nucleus, the N-dimethylaminopropyl side chain of chlorpromazine undergoes demethylation and is metabolized to an N-oxide or sulfoxide derivative. These metabolites may be excreted as their 0-glucouronides, with small amounts of ethereal sulfates of the mono- and dihydroxy derivatives. The major metabolites found in urine are the monoglucouronide of N-demethylchlorpromazine and 7-hydroxychlorpromazine [2]. Although the plasma half life of chlorpromazine itself has been reported to be few hours, the elimination of metabolites may be very prolonged [8, 22-24]. 

The work that has been done with chlorpromazine, haloperidol, and pimozide suggests that these drugs are metabolized more rapidly in children than in adults (Morselli et ah, 1982 Sallee et ah, 1987 Furlanut et ah, 1990). In addition, it appears that larger doses of chlorpromazine and haloperidol per body weight are needed in young people to achieve the same plasma concentrations as those in adults (Morselli et ah, 1979 Rivera-Calimlim et ah, 1979). 

Experimentally induced obstructive jaundice in animals (by ligation of bile ducts) decreases rate of metabolism of certain drugs like hexobarbitone, chlorpromazine, codeine etc. 

Once first-pass metabolism has occurred, metabolites are excreted into the bile and then the small bowel. Those that are lipid soluble are reabsorbed into the portal circulation, eventually entering the systemic circulation. These metabolites may have a similar or substantially different pharmacological profile from their parent drug. For example, chlorpromazine undergoes extensive hepatic biotransformation and has 168 theoretical metabolites, 70 of which have been identified in plasma and... 

Most antipsychotic drugs are readily but incompletely absorbed. Furthermore, many undergo significant first-pass metabolism. Thus, oral doses of chlorpromazine and thioridazine have systemic availability of 25-35%, whereas haloperidol, which has less first-pass metabolism, has an average systemic availability of about 65%. 

Chlorpromazine appears to be variably absorbed and is metabolized in the gut as well as in the liver, where it can accelerate its own hepatic metabolism or conjugation. After being absorbed, the drug was widely distributed in the body and its lipophilicity allowed it to achieve sufficient intramembrane concentrations to influence the stability or fluidity of cell membranes. 

Various factors may account for the variability in response to neuroleptics. These include differences in the diagnostic criteria, concurrent administration of drugs which may affect the absorption and metabolism of the neuroleptics (e.g. tricyclic antidepressants), different times of blood sampling, and variations due to the different type of assay method used. In some cases, the failure to obtain consistent relationships between the plasma neuroleptic concentration and the clinical response may be explained by the contribution of active metabolites to the therapeutic effects. Thus chlorpromazine, thioridazine, levomepromazine (methotrime-prazine) and loxapine have active metabolites which reach peak plasma concentrations within the same range as those of the parent compounds. As these metabolites often have pharmacodynamic and pharmacokinetic activities which differ from those of the parent compound, it is essential to determine the plasma concentrations of both the parent compound and its metabolites in order to establish whether or not a relationship exists between the plasma concentration and the therapeutic outcome. 

Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, interact with drugs including clarithromycin, warfarin, phenelzine, benzotropine, chlorpromazine, diazepam, and cyproheptadine. Cigarette smokers metabolize SSRIs faster. 

The antipsychotic chlorpromazine is a prototype heptotoxicant for production of cholestasis. Pleiotropic effects of chlorpromazine on membrane permeability and associated ion gradients and microfilament-mediated canalicular contraction have been attributed to detergent effects. Valproic acid, an anticonvulsant, is associated with microvesicular steatosis. Inhibition of mitochondial fatty acid (S-oxidation is an important component of this toxic effect and is apparently related to carnitine availability as evidenced by the protection afforded by L-carnitine supplements. The hypolipidemic drugs clofibrate, fenofibrate, and gemfibrozil are peroxisome prolif-erators in rodent liver, but not in humans. Isoniazid, an antibiotic used to treat tuberculosis, exhibits an approximately 1 % incidence of hepatotoxicity. Although toxicity is known to be metabolism-dependent and protein adduction has been well-... 

The anticholinergic effects of imipramine and other tricyclic antidepressants can delay gastrointestinal motility enough to interfere with the absorption of various other drugs. Such was the case in an experimental study of the absorption of levodopa in four healthy subjects (177). It is likely that this effect may interfere with absorption of other drugs, especially those, such as chlorpromazine, that are extensively metabolized in the gut. 

The effects of neuroleptic drugs on serum lipids in adults have been reviewed (439). Haloperidol and the atypical neuroleptic drugs ziprasidone, risperidone, and aripipra-zole, are associated with lower risks of hyperlipidemia, whereas chlorpromazine, thioridazine, and the atypical drugs quetiapine, olanzapine, and clozapine are associated with higher risks. Treatment of the metabolic disturbances caused by neuroleptic drugs has also been reviewed (440). 

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