Inhibitory effects of psychotropic drugs on mexiletine metabolism in human liver microsomes: prediction of in vivo drug interactions.
Mexiletine, an anti-arrhythmic agent, is used for the control of ventricular arrhythmias and for neuropathic pain from cancer or diabetes mellitus. It is sometimes used together with psychotropic drugs in patients with depression, schizophrenia or sleep disorder. It is metabolized mainly by cytochrome P450 (CYP) 2 D 6 and, to a minor extent, by CYP1A2. To predict possible drug interactions between mexiletine and psychotropic drugs, the inhibitory effects of 14 psychotropic drugs (phenytoin, carbamazepine, fluvoxamine, paroxetine, fluoxetine, citalopram, sertraline, imipramine, desipramine, haloperidol, thioridazine, olanzapine, etizolam, and quazepam) on mexiletine metabolism in human liver microsomes were determined. Fluoxetine (Ki=0.6+/- 0.1 microM), sertraline (Ki=7.6+/- 0.8 microM) and desipramine (Ki=3.2+/- 0.5 microM) competitively inhibited the mexiletine p-hydroxylation in human liver microsomes. Thioridazine (Kis=0.5+/- 0.2 microM; Kii =3.6+/-1.6 microM) and paroxetine (Kis=1.7+/- 0.7 microM; Kii=3.6+/- 0.9 microM) exhibited a mixed-type inhibition (competitive and non-competitive) toward mexiletine p-hydroxylation in human liver microsomes. The changes of the in vivo clearance of mexiletine by the psychotropic drugs were predicted by 1+(I/Ki) using the in vitro Ki and unbound inhibitor concentrations in liver. The values were calculated as 2.4 for paroxetine, 5.5 for fluoxetine, 1.1 for sertraline, 2.8 for desipramine and 2.2 for thioridazine. In addition, paroxetine exhibited a mechanism-based inactivation with Ki=0.7 microM and Kinact=0.15 min(-1). The present study predicted the possibility of drug interactions between mexiletine and paroxetine, fluoxetine, desipramine, and thioridazine in clinical use.
Hara
Y
Y
Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Nakajima
M
M
Miyamoto
K-I
KI
Yokoi
T
T
D000889:Anti-Arrhythmia Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006900:Hydroxylation; D008657:Metabolic Clearance Rate; D008801:Mexiletine / Q000378:metabolism* / Q000493:pharmacokinetics; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism*; D011237:Predictive Value of Tests; D011619:Psychotropic Drugs / Q000378:metabolism* / Q000493:pharmacokinetics
D000889:Anti-Arrhythmia Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D011619:Psychotropic Drugs; D008801:Mexiletine; D019389:Cytochrome P-450 CYP2D6