Premium
PII‐62
Author(s) -
Spenard J.,
Lin J.,
Shen H.,
Yuska B.,
Chien B.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.187
Subject(s) - cyp2a6 , pharmacology , cyp2b6 , tolbutamide , chlorzoxazone , dextromethorphan , chemistry , cyp1a2 , cyp2d6 , cyp3a4 , cyp2c19 , drug interaction , cyp2c9 , drug metabolism , isozyme , cyp2c8 , phenacetin , microsome , cytochrome p450 , cyp2e1 , pharmacokinetics , drug , biochemistry , metabolism , in vitro , medicine , enzyme , insulin
AIMS Itopride, a new prokinetic drug, is mainly metabolized by FMO3. This in vitro study assessed the inhibitory potential of itopride on the main human CYP450 drug metabolizing isozymes. METHODS The isozymes activity was evaluated in pooled human hepatic microsomes at itopride concentration up to 100 μM. Probe substrates, phenacetin for CYP1A2, coumarin for CYP2A6, bupropion for CYP2B6, paclitaxel for CYP2C8, tolbutamide for CYP2C9, S‐mephenytoin for CYP2C19, dextromethorphan for CYP2D6, chlorzoxazone for CYP2E1, midazolam and testosterone for CYP3A4/5 were used. The formation of the metabolites reflected CYP450 activity. Positive controls were also used for each isozyme. RESULTS Itopride showed no inhibition on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, CYP3A4/5 activities at 100 μM. The percent of control enzyme activity was 93%, 106%, 73%, 101%, 105%, 104%, 92%, 99%, and 107% when tested at 100 μM, respectively. Itopride was a CYP2D6 inhibitor with calculated IC 50 value of 8.81 μM. Inhibition around the usual Cmax of itopride at therapeutic concentration (0.62 μM) was about 30%. DISCUSSION/CONCLUSIONS Itopride has a small inhibitory effect on CYP2D6. Since the IC 50 value is about 10 times higher than the Cmax and the other isozymes are not affected, the clinical significance of the inhibitory effect on the metabolism of drug by CYP2D6 will be minimal for most patients. Itopride will not inhibit the metabolism of drugs relying on CYP3A4 or isoenzymes other than CYP2D6. Clinical Pharmacology & Therapeutics (2005) 79 , P52–P52; doi: 10.1016/j.clpt.2005.12.187