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Caffeine based measures of CYP1A2 activity correlate with oral clearance of tacrine in patients with Alzheimer's disease
Author(s) -
Fontana Robert J.,
DeVries Tina M.,
Woolf Thomas F.,
Knapp Margaret J.,
Brown AS,
Kaminsky Laurence S.,
Tang BingKuo,
Foster Norman L.,
Brown Richard R.,
Watkins Paul B.
Publication year - 1998
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1998.00776.x
Subject(s) - tacrine , caffeine , cyp1a2 , pharmacology , medicine , pharmacokinetics , metabolite , oral administration , chemistry , metabolism , enzyme , acetylcholinesterase , biochemistry , cytochrome p450
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 [ 13 C‐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 13 CO 2 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.