Evaluation of Caffeine as an In Vivo Probe for CYP1A2 Using Measurements in Plasma, Saliva, and Urine

Abstract

Twenty-five healthy volunteers were given 100 mg caffeine orally and several estimates of cytochrome P450 1A2 (CYP1A2) activity were evaluated. The validation was performed by correlation of different parameters in plasma, saliva, and urine to two measures of caffeine clearance, CL(oral) and CL(137X-->17X) that served as standards of reference. Two subjects were excluded because of noncompliance with a caffeine-free diet. In the remaining 23 subjects, both plasma and saliva total clearances of caffeine were highly correlated 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 CL(oral) and CL(137X-->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-dimethylxanthine (paraxanthine) and 137X is 1,3,7-trimethylxanthine (caffeine). Additionally, the ratio (AFMU + 1U + 1X + 17U + 17X)/137X in a 0-24 hours urine sampling showed the highest correlation with CL(137X-->17X) (r(s) = 0.85, p < 0.001) where AFMU is 5-acetylamino-6-formylamino-3-methyluracil, 1U is 1-methyluracil, 1X is 1-methylxanthine, and 17U is 1,7-dimethyluric acid. The 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 urinary (AFMU + 1U + 1X + 17U + 17X)/137X ratio during a sampling interval of at least 8 hours, starting at time zero since caffeine intake. These indices are simple, reliable, and relatively inexpensive estimates of CYP1A2 activity to be used in the study of human populations.

Correlation of Cytochrome P450 (CYP) 1A2 Activity Using Caffeine Phenotyping and Olanzapine Disposition in Healthy Volunteers

“…The metabolic pathways of caffeine are complex but involve the formation of three principal metabolites: theobromine (3,7-dimethyl xanthine [37X]), theophylline (1,3-dimethylxanthine [13X]), and paraxanthine (1,7-dimethylxanthine [17X]). Each of these metabolites are primarily formed by cytochrome (CYP) P450 1A2 (Carrillo et al, 2000). Conversion to the 17X metabolite comprises about 80% of the metabolic pathway for caffeine.…”

“…The metabolic pathways to the 37X and 13X metabolites are also influenced by CYP2E1 (Sinues et al, 1999). Caffeine has become popular as a metabolic probe for CYP1A2 activity in humans (Carrillo et al, 2000); it is one of the major P450 cytochromes in the liver and accounts for 15% of the total P450 content.…”

“…In addition to caffeine, clinically important psychotropic medications such as olanzapine, clozapine, haloperidol, thioridazine, imipramine, clomipramine, fluvoxamine, and tacrine are completely or partially metabolized by this enzyme (Carrillo et al, 2000;Callaghan et al, 1999;Bertilsson et al, 1994;Spigset et al, 1999a;Otani and Aoshima, 2000). Thus, interindividual variability in CYP1A2 activity may alter the pharmacokinetics of these medications and influence response to therapy, including toxicities such as tardive dyskinesia with older (typical) antipsychotics (Carrillo et al, 2000;Kelly et al, 1999;Basile et al, 2000;Ou-Yang et al, 2000).…”

“…Thus, interindividual variability in CYP1A2 activity may alter the pharmacokinetics of these medications and influence response to therapy, including toxicities such as tardive dyskinesia with older (typical) antipsychotics (Carrillo et al, 2000;Kelly et al, 1999;Basile et al, 2000;Ou-Yang et al, 2000).…”

Alternative Sampling Strategies for Cytochrome P450 Phenotyping

“…Furthermore, in a study involving 25 patients undergoing hepatectomy, significant correlations were found between in vivo parameters of CYP1A2 activity, being caffeine clearance and paraxanthine/caffeine ratios (3 and 6 h post-dose) in oral fluid or plasma, and in vitro parameters, being caffeine 3-demethylation and relative CYP1A2 content in liver microsomes [13]. Since then, the validity of oral fluid for CYP1A2 phenotyping was corroborated by several other studies [81][82][83][84][85][86][87] and, consequently, this approach has been widely applied to assess CYP1A2 activity in various settings [61,85,86,[88][89][90][91][92][93][94][95][96][97][98].…”