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

Abstract

Aims To study the potential utility of caffeine based probes of CYP1A2 enzyme activity in predicting the pharmokinetics of tacrine in patients with Alzheimer's disease. Methods The pharmokinetics of a single 40 mg oral dose of tacrine were measured in 19 patients with Alzheimer's disease. Each patient also received 2 mg kg−1 [13C‐3‐methyl] caffeine orally and had breath and urine samples collected. Results Tacrine oral clearance (CL F−1 kg−1 ), which varied 15‐fold among the patients, correlated significantly with the 2 h total production of 13CO2 in breath (r=0.56, P=0.01), and with each of two commonly used urinary caffeine metabolite ratios: the raxanthine/caffeine ratio’ (1,7X+1, 7U)/1,3,7X) (r=0.76, P=0.0002) and the ‘caffeine metabolic ratio’ (AFMU+1X+1U)/1, 7U)(r=0.76, P=0.0001). Conclusions These observations support a central role for CYP1A2 in the in vivo disposition of tacrine and the potential for drug interactions when tacrine treated patients receive known inducers or inhibitors of this enzyme. The magnitude of the correlations we observed, however, are probably not suffcient to be clinically useful in individualizing tacrine therapy.

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

“…In fact, the apparent oral clearance of tacrine also correlated with the plasma caffeine metabolic ratio, but only in the second study period. These results corroborate the findings of Fontana et al [ 29], and further support a role of CYP1A2 in tacrine metabolism. Although statistically significant, the low degree of correlation between tacrine clearance and measures of CYP1A2 activity may be explained by the known intraindividual variation in CYP1A2 over time.…”

“…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. The caffeine breath test and two urinary caffeine metabolic ratios were shown to correlate with tacrine oral clearance.…”

The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo

“…The coadministration of echinacea and theophylline may result in an increased incidence of toxicity resulting from increased serum theophylline concentrations. Other CYP1A2 substrates that have adverse‐effect issues, such as cyclobenzaprine, tacrine, and clozapine, may be affected by echinacea coadministration 62 , 63 , 64 , 65 , 66 , 67…”

The Current State of Knowledge on Age, Sex, and Their Interactions on Clinical Pharmacology

“…Population studies of patients with amyotrophic lateral sclerosis also showed 32% lower clearance in women compared with men 73 . Breath test phenotyping with caffeine correlated with oral clearance of tacrine, a CYP1A substrate, in patients with Alzheimer's disease, but sex differences were not detected 74 . Ethnic polymorphic differences may also confound sex effects as shown by observations of sex differences found only in Chinese for phenacetin clearance 75 …”