THEOPHYLLINE HAS NO ADVANTAGES OVER CAFFEINE AS A PUTATIVE MODEL-DRUGFOR ASSESSING CYP1A2 ACTIVITY IN HUMANS

Aims The cytochrome P4501A2 (CYP1A2) catalyses the metabolism of a num ber of clinically used drugs, and thus there is an interest in determi ning the activity of CYP1A2 in patients before treatment with CYP1A2 s ubstrates. Caffeine is the most commonly used model drug to assess CYP 1A2 function, but due to the complex metabolism of caffeine, there is a need for an alternative drug to use as an index of CYP1A2 activity. In this study the CYP1A2 substrate theophylline was tested as a possib le alternative to caffeine as a model drug for CYP1A2. Methods Twelve healthy volunteers ingested 200 mg of caffeine, and the caffeine metab olic ratios (CMR), CMR(urine)=(AFMU+1MX+1MU)/17DMU and CMR(plasma)=17D MX/137TMX were determined 6 h after drug intake. After a period of abo ut 2 months the volunteers ingested 257 mg theophylline and blood samp les were drawn and urine was collected during the following 48 h. The oral and partial clearances of theophylline were calculated via N-deme thylation and 8-hydroxylation. The theophylline metabolic ratios, 1MU/ 13DMX and 3MX/13DMX being evaluated as indices of CYP1A2 catalysed N-d emethylation and 13DMU/13DMX as an index of party CYP1A2 catalysed 8-h ydroxylation, were estimated in 0-12 h, 0-24 h and 0-48 h urine sample s, and in plasma and spot urine samples 6 h after the intake of theoph ylline. Results The theophylline plasma ratios for the N-demethylation pathways correlated with the oral clearance of theophylline (r(s)=0.8 81-0.934, P<0.001) and with the respective formation clearances of the metabolites (r(s)=0.712-0.925, P<0.05). Furthermore, all of the theop hylline plasma ratios correlated with the caffeine plasma ratio (r(s)= 0.645-0.663, P<0.05). None of the caffeine metabolic ratios and none o f the 6 h urinary theophylline ratios correlated with the oral or the partial clearances of theophylline (r(s)=0.042-0.556, P>0.05). The the ophylline 0-12 h urine ratios correlated with the oral clearance of th eophylline (r(s)=0.677-0.757, P<0.05) and with the respective formatio n clearances of the metabolites (r(s)=0.705-0.750, P<0.05). However, n one of the theophylline urine ratios correlated with any of the caffei ne metabolic ratios. Conclusions In summary the theophylline 6h plasma and 0-12 h urine ratios 1MU/13DMX and 3MX/13DMX, both reflecting N-de methylation seem to be predictors of the CYP1A2 mediated metabolism of theophylline, whereas only the plasma ratio correlated with the caffe ine plasma 17DMX/137TMX ratio. Thus, it would appear that the plasma t heophylline N-demethylation ratios are superior to the urine ratios as indices of CYP1A2 activity. However, because in some individuals the concentrations of theophylline metabolites in plasma were close to the limit of detection, it is concluded that theophylline does not have m arked advantages over caffeine as a model drug for assessing CYP1A2 ac tivity.