Prediction of drug-drug interactions of zonisamide metabolism in humans from in vitro data

  title={Prediction of drug-drug interactions of zonisamide metabolism in humans from in vitro data},
  author={Hiromitsu Nakasa and H. Nakamura and S Ono and M Tsutsui and Masahiro Kiuchi and Shigeru Ohmori and Mitsukazu Kitada},
  journal={European Journal of Clinical Pharmacology},
Objective: The purposes of this study were to identify the P450 enzyme (CYP) responsible for zonisamide metabolism in humans by using expressed human CYPs and to predict drug interaction of zonisamide in vivo from in vitro data. Methods: Ten expressed human CYPs and human liver microsomes were used in the experiments for the identification of enzymes responsible for zonisamide metabolism and for the prediction of drug-drug interactions of zonisamide metabolism in humans from in vitro data… 
Application of CYP3A4 in vitro data to predict clinical drug-drug interactions; predictions of compounds as objects of interaction.
It is demonstrated that the use of rhCYPs with SIMCYP provides a robust in vitro system for predicting the likelihood and magnitude of changes in clinical exposure of compounds as a consequence of CYP3A4 inhibition by a concomitantly administered drug.
Update on the Genetic Polymorphisms of Drug-Metabolizing Enzymes in Antiepileptic Drug Therapy
The state of research on the effects of mutations of drug-metabolizing enzymes on the pharmacokinetics and pharmacodynamics of AED therapies is summarized and future directions for the dose-adjustment of A ED are discussed.
Identification of cytochrome P-450 isoform(s) responsible for the metabolism of pimobendan in human liver microsomes.
It is concluded that CYP1A2 is one of the major enzymes responsible for the O-demethylation of pimobendan and CYP3A may make a minor contribution at clinically relevant concentrations of the drug.
A Mechanistic Approach to Antiepileptic Drug Interactions
  • G. Anderson
  • Biology, Medicine
    The Annals of pharmacotherapy
  • 1998
By understanding the mechanisms of drug interactions, the pharmacist can play a key role in patient care by anticipating and preventing AED drug interactions.
Effects of the Antifungal Agents on Oxidative Drug Metabolism
The interactions of ketoconazole with cyclosporin and tacrolimus have been applied for therapeutic purposes to allow a lower dosage and cost of the immunosuppressant and a reduced risk of fungal infections.
Population Estimation Regarding the Effects of Cytochrome P450 2C19 and 3A5 Polymorphisms on Zonisamide Clearance
It is demonstrated that the CYP2C19 genotype affects the ZNS metabolism in Japanese epileptic subjects and the clinical relevance of these changes remains to be explored in future studies.
Quantitative Drug Interactions Prediction System (Q-DIPS)
A computerised application, the quantitative drug interactions prediction system (Q-DIPS), to make both qualitative deductions and quantitative predictions on the basis of a database containing updated information on CYP substrates, inhibitors and inducers, as well as pharmacokinetic parameters is developed.
Effect of micafungin on cytochrome P450 3A4 and multidrug resistance protein 1 activities, and its comparison with azole antifungal drugs
It is suggested that micafungin and amphotericin B would be unlikely to cause drug‐drug interactions by inhibition of CYP3A4 and MDR1 and the physicochemical mechanisms involved and impact on clinical treatment should be studied further.
Effects of CYP2C19 and P450 Oxidoreductase Polymorphisms on the Population Pharmacokinetics of Clobazam and N-Desmethylclobazam in Japanese Patients With Epilepsy
The results suggest that determining the CYP2C19 and/or POR genotypes is helpful for obtaining appropriate serum CLB and N-CLB concentrations and preventing an overdose when starting CLB therapy.


Use of In Vitro and In Vivo Data to Estimate the Likelihood of Metabolic Pharmacokinetic Interactions
A database containing information about the clearance routes for over 300 drugs from multiple therapeutic classes, including analgesics, anti-infectives, psychotropics, anticonvulsants, cancer chemotherapeutics, gastrointestinal agents, cardiovascular agents and others, was constructed to assist in the semiquantitative prediction of the magnitude of potential interactions with drugs under development.
Human liver carbamazepine metabolism. Role of CYP3A4 and CYP2C8 in 10,11-epoxide formation.
Pharmacokinetic Interactions Between Antiepileptic Drugs
Antiepileptic drug interactions represent a common clinical problem which has been compounded by the introduction of many new compounds in recent years, and some need only careful clinical monitoring, but others require prompt dosage adjustment.
Characterization of human liver microsomal cytochrome P450 involved in the reductive metabolism of zonisamide.
The metabolism of zonisamide to SMAP was almost completely inhibited by anti-P450 3A4 antibody but not by anti -P450 2C9 or anti- P450 2D6 antibodies, suggesting that the amount of P 450 3A enzyme may be a major factor influencing the level of metabolism ofZonisamideto SMAP in human liver microsomes.
Rat liver microsomal cytochrome P-450 responsible for reductive metabolism of zonisamide.
Results indicate that cytochrome(s) P-450 belonging to P- 450 3A subfamily may be predominantly responsible for the reductive metabolism of zonisamide in rat liver microsomes.
Metabolism of the anticonvulsant agent zonisamide in the rat.
  • D. Stiff, M. Zemaitis
  • Chemistry, Biology
    Drug metabolism and disposition: the biological fate of chemicals
  • 1990
The metabolism of zonisamide primarily involves reductive and conjugative mechanisms, with oxidation of this compound being of minor metabolic significance.
Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians.
The results presented in this study provide useful information for the study of drug biotransformation in humans and for the basis of drug toxicities, carcinogenesis and teratogenesis.
Reductive metabolism of the anticonvulsant agent zonisamide, a 1,2-benzisoxazole derivative.
Metabolism of zonisamide in vitro by hepatic subcellular fractions and cultured gastrointestinal flora produced a single metabolite, 2-(sulphamoylacetyl)-phenol (2-SMAP), by reductive cleavage of the 1,2-benzisoxazole ring.
Reductive metabolism of the anticonvulsant agent zonisamide, a 1,2-benzisoxazole derivative
The metabolism of zonisamide in vitro was characterized through aerobic and anaerobic incubations with rat liver subcellular fractions and cultured gastrointestinal microflora and produced a single metabolite, 2-(sulphamoylacetyl)-phenol (2-SMAP), by reductive cleavage of the 1,2-benzisoxazole ring.