Chlorpromazine metabolism

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. 

Sulfur is readily oxidized, nonenzymatically as well as enzymatically (Scheme 11.21). Chlorpromazine metabolism provides an example of S-oxidation by CYP3A (Scheme 11.22). Chlor promazine is also metabolized by N-oxidation and N-dealkylation pathways, resulting in a multiplicity of excreted products. 

Forrest FM, Forrest IS, SerraMT. Modification of chlorpromazine metabolism some other drugs fiequentfy administered to psychiatric patients. Biol P dnatry (1970) 2, 53-8. 

AC ADME ANS AUC BA/BE BBB BBM BBLM BCS BLM BSA CE CHO CMC CPC CPZ CTAB CV DA DOPC DPPC DPPH aminocoumarin absorption, distribution, metabolism, excretion anilinonaphthalenesulfonic acid area under the curve bioavailability-bioequivalence blood-brain barrier brush-border membrane brush-border lipid membrane biopharmaceutics classification system black lipid membrane bovine serum albumin capillary electrophoresis caroboxaldehyde critical micelle concentration centrifugal partition chromatography chlorpromazine cetyltrimethylammonium bromide cyclic votammetry dodecylcarboxylic acid dioleylphosphatidylcholine dipalmitoylphosphatidylcholine diphenylpicrylhydrazyl... 

Phenothiazines The phenothiazines (PTZs) undergo extensive metabolism. Metabolic routes include S-oxidation, aromatic hydroxylation, N-dealkylation, N-oxidation, and a combination of these processes. Chlorpromazine, for example, possesses 168 possible metabolites, a large proportion of which are pharmacologically active compounds. The development of an HPLC assay capable of resolving a large number of these metabolites is virtually impossible and assays that permit the simultaneous determination of the parent compound and a selected number of active metabolites must suffice. The PTZ group of compounds includes chlorpromazine, thioridazine, fluphenazine, and perphenazine. 

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). 

There are several antipsychotics that are substrates to CYP2D6 (von Bahr et ah, 1991 Jerling et ah, 1996 Ring et ah, 1996 (Fang and Gorrod, 1999 Flockhart and Oesterheld, 2000) (Table 26.3). Moreover, several antipsychotics may act as inhibitors of CYP2D6-mediated biotransformation. These include thioridazine, chlorpromazine, haloperidol, fluphenazine, and pimozide (Desta et ah, 1998 Shin et ah, 1999). Of particular salience is the fact that the serotonin selective reuptake inhibitors (SSRIs) fluoxetine and paroxetine are metabolized to a significant extent by this isoenzyme. 

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 Blockade of D2 receptors >> 5 2 receptors .-Receptor blockade (fluphenazine least) muscarinic (M)-receptor blockade (especially chlorpromazine and thioridazine) Hx-receptor blockade (chlorpromazine, thiothixene) t central nervous system (CNS) depression (sedation) t decreased seizure threshold t QT prolongation (thioridazine) Psychiatric schizophrenia (alleviate positive symptoms), bipolar disorder (manic phase) nonpsychiatric antiemesis, preoperative sedation (promethazine) pruritus Oral and parenteral forms, long half-lives with metabolism-dependent elimination Toxicity Extensions of effects on a - and M- receptors blockade of dopamine receptors may result in akathisia, dystonia, parkinsonian symptoms, tardivedyskinesia, and hyperprolactinemia... 

Chlorpromazine is a tranquilizing and antiemetic agent that may cause a number of side effects in the circulatory and nervous system and adverse effects on blood cells, skin, and the eye. Recent studies suggest a possible genotoxic activity for chlorpromazine, whereas it has been established that certain reactive metabolic intermediates are capable of binding with macromolecules including DNA. 

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. 

Moreover, nitrones can be generated from N-hydroxy products during extraction into an organic solvent, such as diethyl ether. The latter contains acetaldehyde as an impurity even after careful distillation. Indeed, nitrones arising as artifacts from the reaction of primary hydroxylamines, metabolically derived from methamphetamine and chlorpromazine, with acetaldehyde upon sample treatment with ether have been identified23,39. Acetone is frequently used as one of the components of the solvent systems applied for TLC analysis. 

Metabolic response for chlorpromazine, fluorouracil, insulin and thyroxin [113,114]... 

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. 

---