THE CAFFEINE BREATH TEST DOES NOT IDENTIFY PATIENTS SUSCEPTIBLE TO TACRINE HEPATOTOXICITY

Therapy with tacrine, a promising new treatment for Alzheimer's diseas e, must be discontinued in up to 15% of patients because of hepatocell ular toxicity. Recent studies using human liver microsomes have sugges ted that a single liver enzyme, cytochrome P450 1A2 (CYP1A2), catalyze s the major route of metabolism and elimination of tacrine, and also c atalyzes the pathway(s) involved in the generation of reactive metabol ites capable of covalent protein binding and cytotoxicity. Because CYP 1A2 activity has been shown to vary up to 60-fold among patients, we p roposed that a convenient measure of CYP1A2 activity, the [C-13 3-meth yl] caffeine breath test (CBT), might be clinically useful in identify ing patients most susceptible to tacrine liver toxicity, To test this hypothesis, we administered the CBT to 37 patients with Alzheimer's di sease before they began treatment with tacrine. Twenty patients receiv ed 2 mg/kg of [C-13 S-methyl] caffeine. The remaining 17 patients rece ived the commercially available CBT kit, which employs a constant 200- mg dose. The activities of two other major drug-metabolizing enzymes ( cytochrome P450 3A4 and 2D6 [CYP3A4 and CYP2D6]) were also measured in these 17 patients. We found that the results obtained from the CBT pr otocol did not predict the peak serum alanine transaminase (ALT) obser ved in the patients. The measured CYP3A4 and CYP2D6 activities also fa iled to predict the susceptible patients, However, the result of the s tandardized-dose CBT correlated well with the logarithm of the steady- state plasma tacrine level obtained in 10 patients (R(2) = .69, P = .0 03), We conclude that the CBT will not be clinically useful in determi ning the subset of patients most susceptible to tacrine hepatotoxicity . However, the correlation we observed between the CBT results and tac rine blood levels is the first evidence supporting a critical role for CYP1A2 activity in the disposition of the drug in vivo.