Serious respiratory infections can increase clozapine levels and contribute to side effects: a case report

Abstract

Clozapine is mainly metabolized by the cytochrome P450 1A2 (CYP1A2), which may be inhibited by serious respiratory infections. This case report supports that a serious respiratory infection may increase clozapine levels and contribute to side effects. Plasma clozapine and norclozapine levels were monitored 17 times during 1 year. The concentration-to-dose ratio (C/D), an index of metabolic activity, was obtained by dividing the sum of plasma clozapine and norclozapine concentration (total clozapine concentration) by clozapine dose. The coefficient of variation (CV) of the total clozapine concentrations was calculated at different doses to provide a measure of the noise associated with determining clozapine concentrations in clinical practice. During a respiratory infection, the patient was taking 600 mg/day of clozapine. Clozapine levels were 1245 ng/ml (norclozapine 472 ng/ml), reflecting a decrease in clozapine metabolism by approximately a factor of 2. The high clozapine levels were associated with side effects (myoclonus and increased sedation). The C/D during the infection was 2.9, while the rest of C/Ds ranged between 1.0 and 1.6. CVs before and after the infection, at different doses, were always lower than 20%. When the level during the infection was included to calculate the CV on 600 mg/day, the CV increased to 54%. The theophylline literature, a prior case report and this case all suggest that if a clozapine patient develops a severe respiratory infection with fever, the psychiatrist must pay particular attention to any signs suggestive of major clozapine toxicity associated to a decrease in clozapine metabolism. If any of these signs appear, the psychiatrist may need to consider cutting the clozapine dose in half until the patient has recovered from the infection.

Introduction

Clozapine is metabolized by several enzymes. The cytochrome P450 3A (CYP3A) appears to be involved in clozapine metabolism Pinninti and de Leon, 1997, Buur-Rasmussen and Brosen, 1999. One or several UDP-glucuronosyltransferases (UGTs) may be also involved in the metabolism of clozapine and its metabolites (de Leon, 2003). However, the cytochrome P450 1A2 (CYP1A2) appears to explain 70% of clozapine metabolism Bertilsson et al., 1994, Buur-Rasmussen and Brosen, 1999. Ozdemir et al. (2002) suggested that CYP1A2 metabolizes both clozapine and its main metabolite, norclozapine. This explains why caffeine (a CYP1A2 substrate) may increase plasma clozapine concentrations Odom-White and de Leon, 1996, Carrillo et al., 1998 and smoking (a CYP1A2 inducer) decreases plasma clozapine concentrations Hasegawa et al., 1993, Ozdemir et al., 2002. Although it has not been well studied, the inductive effects of smoking on CYP1A2 (and UGTs) are explained by increased enzyme synthesis and probably take several weeks to disappear after smoking cessation. The published case reports of clozapine toxicity after smoking cessation suggest that the increased metabolic enzyme levels after smoking cessation take at least 2-4 weeks to decrease, resulting in clozapine toxicity unless the dose is adjusted McCarthy, 1994, Skogh et al., 1994, Zullino et al., 2002. A study in caffeine response suggests that acute smoking cessation (<84 h) may not be long enough to produce obvious effects on CYP1A2 substrates response (Hughes et al., 1999).

Respiratory infections may inhibit CYP1A2. Decreased theophylline clearance (mediated by CYP1A2 inhibition) has been described in some children with upper respiratory infections and in adults with fever and pneumonia (Chang et al., 1978). The mechanism is not completely understood, but the release of cytokines during the infection appears to decrease the activity and synthesis of CYP1A2 (Abdel-Razzak et al., 1993).

This CYP1A2 inhibition associated with respiratory infections probably has clinical significance in some cases of patients taking CYP1A2 substrates. In a medical records review of 2254 asthmatic children, Shilalukey et al. (1993) suggested that when a child taking theophylline develops an upper respiratory infection, the theophylline dose should be decreased almost by half. Similarly, a recent case report also suggested that bacterial pneumonia can increase clozapine concentrations (Raaska et al., 2002). This new case report supports that a serious respiratory infection may increase clozapine levels and contribute to side effects.