Inhibition kinetics of theophylline metabolism by mexiletine and its metabolites.
To further characterize the mode of drug interaction between theophylline (TP) and mexiletine (ME), in vitro kinetic studies were carried out using rat liver microsomes and 9000 x g supernatant. The kinetic study revealed that the Km value and Vmax/Km ratio for the metabolic conversion of TP to 1,3-dimethyluric acid (1,3-DMU) were the second lowest and the highest, respectively, of four metabolic pathways. Thus, the rank of efficiency of the oxidative metabolism by microsomal cytochrome P-450 (P-450) isozymes was TP to 1,3-DMU > TP to 1-methylxanthine (1-MX) > TP to 3-MX > 1,3-DMU to 1-methyluric acid, suggesting that the isozyme metabolizing TP would have a higher affinity for the oxidation at the 8-position in TP molecules than at the 1- and 3-positions. Lineweaver-Burk plots showed that the conversion of TP to 3-MX and to 1,3-DMU was inhibited competitively by ME and its metabolites, and that the pathway of TP to 1-MX was inhibited noncompetitively. In consideration of the Ki values calculated, it seems probable that deamino-p-hydroxy ME (DApHME) might be the most potent inhibitor of the metabolic pathways of TP, and that the rank order of inhibition is approximately DApHME > p-hydroxy ME > deamino-hydroxymethyl ME > ME > hydroxymethyl ME, with some exceptions. The mechanism of the interaction between TP and ME is probably due to the metabolic antagonism in the liver, and TP, ME and their metabolites share some of the same metabolic pathways, mediated by P-450 isozymes.
Ogiso
T
T
Faculty of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, Japan.
Iwaki
M
M
Uno
S
S
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003640:Dealkylation; D003864:Depression, Chemical; D006900:Hydroxylation; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008801:Mexiletine / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D013806:Theophylline / Q000378:metabolism*
D007527:Isoenzymes; D008801:Mexiletine; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline