CAFFEINE AS A PROBE FOR CYP1A2 ACTIVITY - POTENTIAL INFLUENCE OF RENAL FACTORS ON URINARY PHENOTYPIC TRAIT MEASUREMENTS

Two established caffeine-based urinary methods for measuring CYP1A2 ac tivity were compared with each other, and also with the systemic clear ance of caffeine which served as a standard of reference for such acti vity. Following a standardized dose, caffeine (137X) and its metabolit es were measured in urine and plasma of 39 healthy subjects. The measu rements allowed determinations of: (1) systemic caffeine clearance (CL (caff)); (2) the caffeine metabolite ratio (AFMU + 1X + 1U)/17U determ ined in an overnight-urine specimen and referred to as CMR, and (3) th e ratio (17X + 17U)/137X measured in urine collected between 4 and 5 h after caffeine intake and referred to as PCUR for 'paraxanthine-caffe ine urinary ratio'. The PCUR showed a bimodal distribution and a relat ively wide variation, CL(caff) and CMR were both normally distributed. The correlation between CL(caff) and CMR was r = 0.77 (p < 0.001), be tween CL(caff) and PCUR r = 0.46 (p < 0.01), and between CMR and PCUR r = 0.40 (p <0.02). The difference between the correlation coefficient s 0.77 and 0.46 was statistically significant (z-test; p < 0.0 5). The well established decrease of caffeine metabolism by oral contraceptiv e use was observed with both CL(caff) and CMR but not with PCUR. Exami nation of possible explanations for the differences between PCUR and C MR led to the finding of a correlation between PCUR and the renal clea rance of caffeine (CL(r)) with r = -0.47 (p < 0.01). Further scrutiny demonstrated that a bimodal or non-normal frequency distribution as sh own by PCUR was also shown by CL, and by urine flow rate. It appears t hat the PCUR method for assessing the in vivo activity of CYP1A2 refle cts renal factors as much as metabolic function. The assignment of 'ph enotypic trait' values to CYP1A2, activity may represent a distortion by renal factors.