Clozapine liver

Liver function test abnormalities are common. If aminotransferases are greater than three times the upper limit of normal, the antipsychotic should be changed to a chemically unrelated antipsychotic. These changes are less common with the SGAs but are reported with risperidone and clozapine. 

Cholestatic hepatitis has been reported with risperidone, and liver function test abnormalities (mostly transient) have been reported with olanzapine and clozapine. 

Many antipsychotics show great interindividual variation in plasma levels and so analysis of therapeutic levels can be important clinically as well as in the research laboratory. In addition, nonresponse to the drugs may actually be due to excessive levels of neuroleptics, a paradoxical situation that requires analysis to identify (Rockland, 1986). Several methods using FID were cited in the previous edition of the Handbook of Neurochemistry but ECD and NPD have both shown utility for the typically low therapeutic levels (Cooper, 1988). GC-FID has been used to analyze levels of clozapine in blood, gastric, and urine samples in fatal cases of overdose with this drug (Ferslew et al., 1998), and olanzapine has been measured in blood and urine samples by GC-NPD in overdoses (Stephens et al., 1998). 4-(4-Chlorophenyl)-4-hydroxypiperidine, a metabolite of haloperidol, was analyzed in urine, plasma, brain, and liver from haloperidol-treated rats by GC-ECD, after derivatization with PFBC under aqueous conditions (Fang et al., 1996). 

Quetiapine (Seroquel). Another atypical antipsychotic, quetiapine has also been approved by the FDA for the treatment of acute mania. It is usually administered twice daily at doses of 150-750mg/day. Like its counterparts, quetiapine is a well-tolerated medication. Its common side effects are drowsiness, dizziness, and headache. It causes less weight gain than olanzapine or clozapine but more than ziprasidone or aripiprazole. Quetiapine also does not cause agranulocytosis nor does it increase the risk of seizures. It can occasionally cause mild changes in liver function tests, but these usually return to normal even if the patient continues taking quetiapine. 

Because of the potential for hematological and hepatic toxicity, carbamazepine should not be administered to patients with liver disease or thrombocytopenia or to those at risk for agranulocytosis. For this reason, carbamazepine is strictly contraindicated in patients receiving clozapine. Because of reports of teratogenicity, including increased risks of spina bifida (Rosa 1991), microcephaly (Bertol-lini et al. 1987), and craniofacial defects (Jones et al. 1989), carbamazepine is relatively contraindicated in pregnant women. Pretreatment evaluation should include a complete blood count and determination of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. 

Recently, a study was conducted to compare the MDF method to PIS and NLS methods in finding oxidative metabolites in biological fluids (Zhu et al., 2004, 2006). In this study, diclofenac and clozapine (Fig. 6.8) were incubated with human liver microsomes and the metabolites generated were then spiked into pooled rat urine and bile followed by analyses using either high-resolution LC- MS -based MDF or triple-quadmpole LC-MS with NLS and PIS. 

Pirmohamed M, Williams D, Madden S, et al. Metabolism and bioactivation of clozapine by human liver in vitro. J Pharmacol Exp Ther 1995 272 984-990. 

Liver damage due to atypical neuroleptic drugs generally occurs within the first weeks of treatment, but the delay is highly variable, being 1-8 weeks for clozapine, 12 days to 5 months for olanzapine, and 1 day to 17 months for risperidone (520). 

A tonic-clonic seizure occurred in a 30-year-old man 4 weeks after he started to take clozapine 400 mg/day (66). This was followed by a large increase in liver enzymes, which had been normal the week before. 

Transient asymptomatic liver enzyme rises are common with clozapine (183). 

A 49-year-old woman (184) took clozapine 300 mg/day and developed lethargy, anorexia, fever, eosinophilia, leukocytosis, and abnormal liver function tests. The serum clozapine concentration was 8595 nmol/1. Clozapine was withdrawn and after 8 days her condition stabilized and low-dose clozapine treatment was successfully restarted with serum monitoring. 

Panagiotis B. Grand mal seizures with liver toxicity in a case of clozapine treatment. J Neuropsychiatry Clin Neurosci 1999 ll(l) 117-8. 

Macfarlane B, Davies S, Mannan K, Sarsam R, Pariente D, Dooley J. Fatal acute fulminant liver failure due to clozapine a case report and review of clozapine-induced hepatotoxicity. Gastroenterology 1997 112(5) 1707-9. 

A mild jaundice, typically occurring early in therapy, may be seen in some patients receiving chlorpromazine. Pruritus is rare. The reaction probably is a manifestation of hypersensitivity, because eosinophilia and eosinophilic infiltration of the liver occur. For uninterrupted drug therapy in a patient with neuroleptic-induced jaundice, it probably is safest to use low doses of a potent, dissimilar agent. Hepatic dysfunction with other antipsychotic agents is uncommon. Clozapine can cause potentially severe ileus and sialorrhea. 

Fan PW, Bolton JL (2001) Bioactivation of tamoxifen to metabolite E quinone methide reaction with glutathione and DNA. Drug Metab Dispos 29 891-896 Fischer V, Haar JA, Greiner L et al (1991) Possible role of free radical formation in clozapine (clozaril)-induced agranulocytosis. Mol Pharmacol 40 846-853 Fisher R, Brendel K, Hanzlik RP (1993) Correlation of metabolism, covalent binding and toxicity for a series of bromobenzene derivatives using rat liver slices in vitro. Chem Biol Interact 88 191-198... 

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