Evaluation of caffeine as an in vivo probe for CYP1A2 using measurements in plasma, saliva, and urine

Twenty-five healthy volunteers were given 100 mg caffeine orally and severa l estimates of cytochrome P450 1A2 (CYP1A2) activity were evaluated. The va lidation was pet-formed by correlation of different parameters in plasma, s aliva, and urine to two measures of caffeine clearance, CLoral and CL137X-- >17X that served as standards of reference. Two subjects were excluded beca use of noncompliance with a caffeine-free diet. In the remaining 23 subject s, both plasma and saliva total clearances of caffeine were highly correlat ed with each other (r(s) = 0.97, p < 0.0001). The ratio 17X/137X restricted to one sampling point taken 4 hours after dose, showed a high correlation (r(s)) with CLoral and CL137X-->17X in plasma (0.84/0.83) and saliva (0.82/ 0.77) (p < 0.0001 for all the correlation values) where 17X is 1,7-dimethyl xanthine (paraxanthine) and 137X is 1,3,7-trimethylxanthine (caffeine). Add itionally, the ratio (AFMU + 1U + 1X + 17U + 17X)/137X in a 0-24 hours urin e sampling showed the highest correlation with CL137X-->17X (r(s) = 0.85, p < 0.001) where AFMU is 5-acetylamino-6-formylamino-3-methyluracil, 1U is 1 -methyluracil, 1X is I-methylxanthine, and 17U is 1,7-dimethyluric acid. Th e major estimates of CYP1A2 activity were significantly less in nonsmoking females, and this probably was related to the use of oral contraceptives in this subpopulation. In summary, among caffeine-based approaches for CYP1A2 , the authors recommend either plasma or saliva 17X/137X ratio and the urin ary (AFMU + 1U + 1X + 17U + 17X)/137X ratio during a sampling interval of a t least 8 hours, starting at time zero since caffeine intake. These indices are simple, reliable, and relatively inexpensive estimates of CYP1A2 activ ity to be used in the study of human populations.