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CYP2J2 metabolizes domperidone in guinea pig hearts
Author(s) -
Michaud V.,
Masseé R.,
Turgeon J.
Publication year - 2005
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.2004.12.177
Subject(s) - domperidone , guinea pig , pharmacology , medicine , dopamine
Background We have shown previously that domperidone is metabolized mainly by the CYP3A4/5 isozymes. Recent studies have indicated that CYP2J2 is abundant in cardiovascular tissues. Preliminary data from our laboratory indicate that guinea pig heart microsomes have the capacity to metabolize domperidone. Purposes The objective of this study was to identify the cytochrome P450 isoforms involved in the metabolism of domperidone in guinea pig hearts. Methods In vitro incubations were conducted with microsomes from baculovirus transfected cells expressing high levels of CYP2J2 (rCYP2J2) and microsomes from guinea pig hearts. Domperidone (1–500 μM) and testosterone (300 μM) were incubated for 45 and 30 minutes, respectively, with various microsomal preparations in the presence of NADPH regenerating system. Formation rate of domperidone major hydroxylated metabolite (M3) and 6βOH‐testosterone were monitored by HPLC with fluorescence and UV detection, respectively. Results Km and Vmax values for the formation of M3‐domperidone were 5 μM and 1.44 nmol/nmolCYP450/min, when incubations were performed with rCYP2J2. Similarly, M3‐domperidone was formed in incubations performed with guinea pig heart microsomes. But, in contrast, no 6βOH‐testosterone was detected in experiments conducted with heart microsomes. Conclusions CYP2J2, in addition to CYP3A4/5 shows catalytic activity towards domperidone. These results suggest the involvement of CYP2J2 in the metabolism of domperidone in the heart. Clinical Pharmacology & Therapeutics (2005) 77 , P75–P75; doi: 10.1016/j.clpt.2004.12.177