CYP-Mediated Clozapine Interactions: How Predictable Are They?

Abstract

Despite the introduction of newer drugs, the atypical antipsychotic clozapine remains the most effective drug in psychotic patients who are resistant to treatment with conventional agents. Optimal therapeutic responses to clozapine have been reported with serum concentrations between 350 microg/L and 1000 microg/L. Clozapine is frequently combined with other drugs to enhance efficacy and reduce adverse reactions but pharmacokinetic interactions can have a significant impact on drug response. The majority of the interactions with clozapine are reported to be mediated by cytochrome P450 (CYP) enzymes. CYP1A2 has a major role in the oxidative metabolism of clozapine, with a minor contribution from CYP3A4, and possibly CYP2D6, CYP2C9 and CYP2C19. Interactions mediated by potent CYP1A2 inhibitors (such as fluvoxamine) or inducers (like cigarette smoke) appear to be consistent, predictable and usually clinically significant. There are many case reports of interactions between clozapine and weak CYP1A2 inhibitors or inducers which are also potent inhibitors or inducers of CYP3A4 or CYP2D6. Researchers often explain these observations on the basis of the CYP1A2 involvement. In addition, there are case reports of clinically significant interactions between clozapine and drugs that are not substrates, inhibitors or inducers of CYP1A2. These interactions are difficult to predict and may not be consistent, as reflected by the conflicting literature reports. Further research to elucidate individual differences in clozapine metabolism, with the potential to detect the dominant roles of CYPs other than CYP1A2, may assist us in predicting these interactions.

Peony-Glycyrrhiza Decoction, an Herbal Preparation, Inhibits Clozapine Metabolism via Cytochrome P450s, but Not Flavin-Containing Monooxygenase in In Vitro Models

“…Clozapine (CLZ) is metabolized to norCLZ and CLZ-N-oxide mainly via hepatic cytochrome P450 (CYP) enzymes (Chetty and Murray, 2007). The present study first examined the kinetic effects of PGD in HLM.…”

“…We found that PGD at 2.5 mg/ml, an effective dose inducing pharmacological and therapeutic response, exerted significant effects in reducing V max and C int and increasing K m values of the two CLZ metabolites, norCLZ and CLZ-N-oxide, indicating that this herbal preparation possesses the capacity to suppress CLZ metabolism in vitro. Of the CYP enzyme systems, CYP1A2 and CYP3A4 play a major role in the metabolism of CLZ, with a minor contribution from other CYP isoforms (Chetty and Murray, 2007). We therefore further examined the effects of PGD on individual CYP activity using recombinantly expressed CYPs.…”

“…Clozapine is metabolized to N-demethylated CLZ (norCLZ) and N-oxygenated CLZ (CLZ-N-oxide) via hepatic cytochrome P450 (CYP) enzymes, mainly CYP1A2, CYP3A4, CYP2D6, CYP2C9, and CYP2C19 (Chetty and Murray, 2007). CYPs also play a critical role in the kinetic interaction between liquorice and peony and conventional drugs (Chen et al, 2002;Wang et al, 2013c;Wu et al, 2012;Zhou et al, 2003).…”

The combined use of risperidone long-acting injection and clozapine in patients with schizophrenia non-adherent to clozapine: a case series

“…Two case reports have suggested that risperidone can increase the serum level of clozapine through inhibiting the CYP enzyme (Koreen et al, 1995;Tyson et al, 1995), but a subsequent study demonstrated that risperidone did not affect the serum clozapine level (Raaska et al, 2002). However, because no consensus on the potential pharmacokinetic risks of combining risperidone and clozapine (Chetty and Murray, 2007) and no confirmation of the interactions between RLAI and clozapine are available yet, potential risks must be considered. The most recent clozapine serum levels obtained from the present cases during RLAI augmentation varied from 44.6 to 233.3 ng/ml (clozapine doses from 100 to 300 mg/day), which is lower than 350 ng/ml, the recommended threshold (Gaertner et al, 2001), and lower than 332.5 AE 188.6 ng/ml, the value obtained from stable schizophrenic patients undergoing clozapine treatment in our clinic (Chang et al, 2008).…”

Therapeutic Drug Monitoring of Clozapine in a Hemodialysed Smoking Patient With Schizophrenia

“…We then investigated the question of drug-drug interaction. 6 The patient was treated with carbamazepine (400 mg/d), a well-known inducer of CYP1A2, but despite its withdrawal, no significant increase of clozapine plasma level occurred. Other treatments (amlodipine, valproic acid, clobazam, sevelamer) are not known to affect clozapine metabolism.…”