Objective: To evaluate mexiletine clearance in a Japanese population and to clarify the roles of CYP2D6 and CYP1A2 in mexiletine disposition.
Methods: Concentrations of serum and urinary mexiletine and its metabolites were determined and mexiletine clearances were estimated in 334 inpatients receiving mexiletine therapy. Concentrations of mexiletine and its metabolites in serum and urine samples were determined by HPLC.
Results: Although interindividual variation of mexiletine clearance was small, the effect of age on mexiletine clearance was comparatively large. Mexiletine clearance in patients with dilated cardiomyopathy (DCM) was decreased when compared with other diagnoses (Non-DCM). The fractional contents of p-hydroxymexiletine (POH) and 2-hydroxymexiletine (OHMEX) in urine amounted to approximately 50%. Almost all of the POH was conjugated, whereas less than one-third of the OHMEX was conjugated. Although no significant differences in POH and OHMEX were observed between patients with DCM and those without, a trend toward an increase in conjugation pathway of DCM patients was observed.
Conclusions: The interindividual variation of mexiletine clearance was small, while the effect of age on the mexiletine clearance in Non-DCM was comparatively large. A significant difference in mexiletine clearance between patients with DCM and those with Non-DCM was observed. Therefore, when mexiletine is administered to patients with DCM, careful monitoring is needed.