The caffeine breath test does not identify patients susceptible to tacrine hepatotoxicity

Abstract

position of the drug in vivo. (HEPATOLOGY 1996;23:1429-Therapy with tacrine, a promising new treatment for 1435.) Alzheimer's disease, must be discontinued in up to 15% of patients because of hepatocellular toxicity. Recent studies using human liver microsomes have suggested that a single liver enzyme, cytochrome P450 1A2 Tacrine (1,2,3,4-tetrahydro-9 acridinamine monohy-(CYP1A2), catalyzes the major route of metabolism and drochloride monohydrate; Cognex, Parke Davis Pharelimination of tacrine, and also catalyzes the pathway(s) maceuticals, Morris Plains, NJ), a potent acetylcholininvolved in the generation of reactive metabolites capa-esterase inhibitor, is the first therapeutic agent shown ble of covalent protein binding and cytotoxicity. Because to have significant benefit in the treatment of cognitive CYP1A2 activity has been shown to vary up to 60-fold deficits in patients with Alzheimer's disease. [1][2][3][4][5] It has among patients, we proposed that a convenient measure been estimated that approximately 3 to 4 million sured CYP3A4 and CYP2D6 activities also failed to predict the susceptible patients. However, the result of the However, susceptibility to tacrine liver toxicity clearly standardized-dose CBT correlated well with the loga-varies greatly in the Alzheimer's population, and at rithm of the steady-state plasma tacrine level obtained least two patients receiving tacrine have developed in 10 patients (R 2 Å .69, P Å .003). We conclude that the clinical jaundice indicative of severe hepatocellular in-CBT will not be clinically useful in determining the sub-jury. 8,9 A liver biopsy obtained in one of these patients set of patients most susceptible to tacrine hepatotoxic-revealed massive centrilobular necrosis. 8 In light of the ity. However, the correlation we observed between the potential risk for serious liver injury and the fact that CBT results and tacrine blood levels is the first evidence patients with serum transaminase elevations are gen-

Caffeine based measures of CYP1A2 activity correlate with oral clearance of tacrine in patients with Alzheimer's disease

“…We reasoned that if CYP1A2 activity is rate limiting in tacrine clearance, the results of these caffeine tests might predict tacrine kinetics in patients. This hypothesis is supported by an incidental observation we made when investigating tacrine liver toxicity [12]. In 39 patients with Alzheimer's disease, we found that CYP1A2 activity, as measured using the [ 13 C‐3‐ N ‐methyl] caffeine breath test, did not identify the individuals most susceptible to tacrine induced liver injury.…”

“…A significant amount of data obtained in in vitro systems supports a central role for CYP1A2 in tacrine metabolism [8, 9, 35]. Since both caffeine and tacrine appear to be largely metabolized by CYP1A2 [7, 8], we believed that the ability to metabolize caffeine should predict the apparent oral clearance of tacrine in patients with AD [12]. In support of our hypothesis, statistically significant correlations between each of the three caffeine test results and the oral clearance of tacrine were demonstrated (Table 1).…”

Tacrine is not an ideal probe drug for measuring CYP1A2 activity in vivo

“…While no correlation was found between the caffeine test and theophylline clearance [ 20], the caffeine test has been shown to correlate with clozapine clearance [ 2]. Likewise, the caffeine breath test has been shown to correlate with the logarithm of the steady‐state plasma tacrine concentration [ 28]. While the present study was in progress, Fontana et al [ 29] published a study on the utility of caffeine based probes of CYP1A2 activity in predicting the pharmacokinetics of tacrine in 19 patients with Alzheimer’s disease.…”

Clinical importance of non-genetic and genetic cytochrome P450 function tests in liver disease

“…Recently, caffeine metabolite levels have been measured in urine in an attempt to monitor CYP1A2 activity ( 67–70), but this method has only been applied to patients with liver disease ( 70). A method using radiolabelled caffeine, in which the level of labelled CO 2 in patients’ breath is measured, has been used for some time ( 71, 72)…”

“…Detailed reviews of CYP3A have been published by Watkins ( 17) and Wilkinson ( 87). Many probe drugs metabolized by CYP3A, including nifedipine ( 88), erythromycin ( 89–91) and lidocaine ( 72, 92–99), have been reported, and there have been numerous reports of the use of erythromycin (breath test) and lidocaine as probe drugs in liver function tests. Huang et al .…”