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Identification of cytochrome P-450 isoenzymes (CYPs) involved in perazine 5-sulphoxidation and N-demethylation was carried out using human liver microsomes and cDNA-expressed human CYPs (Supersomes). In human liver microsomes, the formation of perazine metabolites correlated significantly with the level of CYP1A2 and ethoxyrezorufin O-deethylase activity, as well as with the level of CYP3A4 and cyclosporin A oxidase activity. Moreover, the formation of N-desmethylperazine also correlated well with S-mephenytoin 4′-hydroxylase activity (CYP2C19). α-Naphthoflavone (a CYP1A2 inhibitor) and ketoconazole (a CYP3A4 inhibitor) significantly decreased the rate of perazine 5-sulphoxidation, while ticlopidine (a CYP2C19 inhibitor) strongly reduced the rate of perazine N-demethylation in human liver microsomes. The cDNA-expressed human CYPs generated different amounts of perazine metabolites, but the preference of CYP isoforms to catalyze perazine metabolism was as follows (pmol of product/pmol of CYP isoform/min): 1A1>2D6>2C19>1A2>2B6>2E1>2A6≈3A4>2C9 for 5-sulphoxidation and 2C19>2D6>1A1>1A2>2B6>3A4>2C9>2A6 for N-demethylation.In the light of the obtained results and regarding the contribution of each isoform to the total amount of CYP in human liver, it is concluded that CYP1A2 and CYP3A4 are the main isoenzymes catalyzing 5-sulphoxidation (32% and 30%, respectively), while CYP2C19 is the main isoform catalyzing perazine N-demethylation (68%). CYP2C9, CYP2E1 CYP2C19 and CYP2D6 are engaged to a lesser degree in 5-sulphoxidation, while CYP1A2, CYP3A4 and CYP2D6 in perazine N-demethylation (6–10%, depending on the isoform). [Copyright &y& Elsevier]

Zolmitriptan is a novel and highly selective 5-HT1B/1D receptor agonist used as an acute oral treatment for migraine. There are few reports regarding the in vitro metabolism of zolmitriptan. Previous studies indicated zolmitriptan was metabolized via CYP1A2 in human hepatic microsomes. In order to study the enzyme kinetics and drug interaction, the metabolism of zolmitriptan and possible drug–drug interactions were investigated in rat hepatic microsomes induced with different inducers. An active metabolite, N-demethylzolmitriptan, was detected and another minor, inactive metabolite that was reported in human hepatic microsomes was not detected in this study. The enzyme kinetics for the formation of N-demethylzolmitriptan from zolmitriptan in rat liver microsomes pretreated with BNF were 96±22 μM (Km), 11±3 pmol min−1 mg protein−1 (Vmax), and 0.12±0.02 μl min−1 mg protein−1 (CLint). Fluvoxamine and diphenytriazol inhibited zolmitriptan N-demethylase activity catalyzed by CYP1A2 (Ki=3.8±0.3 and 3.2±0.1 μM, respectively). Diazepam and propranolol elicited a slight inhibitory effect on the metabolism of zolmitriptan (Ki=70±11 and 90±18 μM, respectively). Cimetidine and moclobemide produced no significant effect on the metabolism of zolmitriptan. Fluvoxamine yielded a kinactivation value of 0.16 min−1, and Ki of 57 μM. The results suggest that rat hepatic microsomes are a reasonable model to study the metabolism of zolmitriptan, although there is a difference in the amount of minor, inactive metabolites between human hepatic microsomes and rat liver microsomes. The results of the inhibition experiments provided information for the interactions between zolmitriptan and drugs co-administrated in clinic, and it is helpful to explain the drug–drug interactions of clinical relevance on enzyme level. This study aso demonstrated that fluvoxamine may be a mechanism-based inactivator of CYP1A2. [Copyright &y& Elsevier]

Cites a study examining the effects of modified cyclodextrins (CD) hydroxypropyl-β-CD and methyl-β-CD on cDNA-expressed human cytochrome P-450 (CYP) activities. Ability of modified CD to inhibit the activities of CYP2C19 and CYP3A4; Enhancement by CD of the CYP2C9 activity by 140 to 176 percent; Inhibition by methyl-β-CD of CYP1A2 and CYP2D6 at higher concentrations.