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

Br J Clin Pharmacol. 1998 Sep;46(3):221-8. doi: 10.1046/j.1365-2125.1998.00776.x.


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 'paraxanthine/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 sufficient to be clinically useful in individualizing tacrine therapy.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Oral
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / urine
  • Caffeine / pharmacokinetics*
  • Caffeine / urine
  • Cholinesterase Inhibitors / adverse effects
  • Cholinesterase Inhibitors / pharmacokinetics*
  • Cytochrome P-450 CYP1A2 / metabolism*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Phosphodiesterase Inhibitors / pharmacokinetics*
  • Phosphodiesterase Inhibitors / urine
  • Predictive Value of Tests
  • Tacrine / adverse effects
  • Tacrine / pharmacokinetics*


  • Cholinesterase Inhibitors
  • Phosphodiesterase Inhibitors
  • Caffeine
  • Tacrine
  • Cytochrome P-450 CYP1A2