Ciprofloxacin increases serum clozapine and N-desmethylclozapine: a study in patients with schizophrenia

Raaska, Kari; Neuvonen, Pertti J.

doi:10.1007/s002280000192

Cited by 85 publications

(41 citation statements)

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“…In fact, the disposition of clozapine covaries with CYP1A2 activity [1]. Elevated serum clozapine concentrations during concomitant CYP1A2 inhibitors¯uvoxamine or cipro¯oxacin further elucidate the role of CYP1A2 [3,19]. Fluvoxamine may increase serum clozapine concentrations by up to tenfold [3].…”

Section: Discussionmentioning

confidence: 96%

Effect of influenza vaccination on serum clozapine and its main metabolite concentrations in patients with schizophrenia

Raaska

Raitasuo

Neuvonen

2001

Eur J Clin Pharmacol

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Section: Discussionmentioning

confidence: 96%

Effect of influenza vaccination on serum clozapine and its main metabolite concentrations in patients with schizophrenia

Raaska

Raitasuo

Neuvonen

2001

Eur J Clin Pharmacol

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“…Thus, drug interactions in which serum levels of CLZ are increased in patients by the CYP1A2 inhibitors and substrates fluvoxamine, ciprofloxacin, and caffeine have been reported widely (Hiemke et al, 1994;Jerling et al, 1994;Raaska and Neuvonen, 2000). Indeed, fluvoxamine decreased CLZ clearance severalfold (Hiemke et al, 1994;Wang et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Interindividual Variation in Relative CYP1A2/3A4 Phenotype Influences Susceptibility of Clozapine Oxidation to Cytochrome P450-Specific Inhibition in Human Hepatic Microsomes

Zhang¹,

D'Esposito²,

Edwards³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The atypical antipsychotic drug clozapine (CLZ) is effective in a substantial number of patients who exhibit treatment-resistance to conventional agents. CYP1A2 is generally considered to be the major enzyme involved in the biotransformation of CLZ to its N-demethylated (norCLZ) and N-oxygenated (CLZ N-oxide) metabolites in liver, but several studies have also implicated CYP3A4. The present study assessed the interplay between these cytochrome P450s (P450s) in CLZ biotransformation in a panel of hepatic microsomal fractions from 14 individuals. The relative activity of P450s 1A2 and 3A4 in microsomes was found to be a major determinant of the relative susceptibility of norCLZ formation to inhibition by the P450-selective inhibitors fluvoxamine and ketoconazole. In contrast, the activity of CYP3A4 alone was correlated with the susceptibility of CLZ N-oxide formation to inhibition by these agents. These findings suggest that both P450s may be dominant CLZ oxidases in patients and that the relative activities of these enzymes may determine clearance pathways. In vivo assessment of CYP1A2 and CYP3A4 activities, perhaps by phenotyping approaches, could assist the optimization of CLZ dosage and minimize pharmacokinetic interactions with coadministered drugs.The atypical antipsychotic agent clozapine (CLZ) is effective in many patients who are resistant to treatment with conventional antipsychotic drugs, such as the phenothiazines and butyrophenones. However, its wider use is limited by interindividual variation in efficacy and toxicity. In vitro evidence suggests that the biotransformation of CLZ to its major metabolites N-desmethyl-CLZ (norCLZ) and CLZ N-oxide is catalyzed by hepatic cytochromes P450 (P450s) and flavin-containing monooxygenases (FMOs) (Pirmohamed et al., 1995). NorCLZ formation has been attributed to CYP1A2 and CYP3A4 (Pirmohamed et al., 1995;Linnet and Olesen, 1997) and CYP1A2 and CYP3A4, as well as the FMOs, catalyze CLZ N-oxygenation in vitro (Pirmohamed et al., 1995;Tugnait et al., 1997).There is wide interindividual variation in serum concentrations of CLZ and its active metabolite norCLZ, and the potential for pharmacokinetic drug-drug interactions in psychotic patients is high because of the likelihood of concurrent drug treatment. There have been numerous clinical reports that coadministration of alternate substrates and inhibitors of CYP1A2, such as the selective serotonin reuptake inhibitor fluvoxamine, fluoroquinolone antibacterials, and caffeine, inhibit CLZ clearance and mediate toxic interactions (Hiemke et al., 1994;Jerling et al., 1994). However, it has also been reported that drugs such as fluoxetine, paroxetine, and erythromycin, which inhibit CYP3A4 rather than CYP1A2, may also precipitate toxicity (Centorrino et al., 1996;Wetzel et al., 1998). The factors that determine individual susceptibility to CYP1A2 and CYP3A4 inhibition that leads to clinical toxicity are presently unclear.In a proportion of patients who receive CLZ therapeutic failure may occur because of rapid el...

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“…Ciprofloxacin is a potent inhibitor of CYP1A2 and a weak inhibitor of CYP3A4 [4,5] . Some npg studies have demonstrated a drug-drug interaction when ciprofloxacin was co-administered with other drugs, including theophylline [6,7] , caffeine [8] , clozapine [9] , methadone [10] and zolpidem [11] . Ciprofloxacin is commonly prescribed with analgesics for the management of infection, pain and inflammation.…”

Section: Introductionmentioning

confidence: 99%

Ciprofloxacin blocked enterohepatic circulation of diclofenac and alleviated NSAID-induced enteropathy in rats partly by inhibiting intestinal β-glucuronidase activity

et al. 2016

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Aim: Diclofenac is a non-steroidal anti-inflammatory drug (NSAID), which may cause serious intestinal adverse reactions (enteropathy). In this study we investigated whether co-administration of ciprofloxacin affected the pharmacokinetics of diclofenac and diclofenacinduced enteropathy in rats. Methods: The pharmacokinetics of diclofenac was assessed in rats after receiving diclofenac (10 mg/kg, ig, or 5 mg/kg, iv), with or without ciprofloxacin (20 mg/kg, ig) co-administered. After receiving 6 oral doses or 15 intravenous doses of diclofenac, the rats were sacrificed, and small intestine was removed to examine diclofenac-induced enteropathy. β-Glucuronidase activity in intestinal content, bovine liver and E coli was evaluated. Results: Following oral or intravenous administration, the pharmacokinetic profile of diclofenac displayed typical enterohepatic circulation, and co-administration of ciprofloxacin abolished the enterohepatic circulation, resulted in significant reduction in the plasma content of diclofenac. In control rats, β-glucuronidase activity in small intestinal content was region-dependent: proximal intestine

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Ciprofloxacin increases serum clozapine and N-desmethylclozapine: a study in patients with schizophrenia

Cited by 85 publications

References 0 publications

Effect of influenza vaccination on serum clozapine and its main metabolite concentrations in patients with schizophrenia

Effect of influenza vaccination on serum clozapine and its main metabolite concentrations in patients with schizophrenia

Interindividual Variation in Relative CYP1A2/3A4 Phenotype Influences Susceptibility of Clozapine Oxidation to Cytochrome P450-Specific Inhibition in Human Hepatic Microsomes

Ciprofloxacin blocked enterohepatic circulation of diclofenac and alleviated NSAID-induced enteropathy in rats partly by inhibiting intestinal β-glucuronidase activity

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