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

Abstract

AimsThe aim of the present study was to examine the CYP1A2 substrate tacrine as a possible alternative to caffeine for assessing CYP1A2 activity in vivo. Methods Eighteen, healthy, nonsmoking men participated. Each volunteer was tested by caffeine (200 mg orally), and caffeine metabolic ratios were calculated. Subsequently, on two occasions, separated by at least 4 weeks, each volunteer was tested with tacrine (40 mg orally). The apparent oral clearance, partial clearances and different metabolic ratios of tacrine were determined. Results The median oral clearances of tacrine in the two study periods were 1893 l h −1 (range: 736-3098) and 1890 l h −1 (range: 438-4175), respectively. The interindividual coefficient of variation was 42% and 49%, respectively. The intraindividual coefficients of variation ranged from 0.28% to 64% (median: 13%).In both study periods, the oral clearance of tacrine correlated with the caffeine urinary metabolic ratio. monohydroxy-, dihydroxy-and phenol glucuronide metabolites [11]. In vitro studies suggest that the formation The CYP1A2 activity exhibits substantial intra-and interindividual variation [7, 8]. Therefore, assessment of of the monohydroxymetabolites (1-hydroxytacrine (1-OH-THA), 2-hydroxytacrine (2-OH-THA) and 4-hydroxy-CYP1A2 activity in patients would be of theoretical value before treatment with CYP1A2 substrates, in tacrine (4-OH-THA)) involves CYP1A2 [12][13][14]. In one study [12], a correlation between the formation of the particular those drugs having a low therapeutic index, and for which clinical dose titration is not feasible (e.g. major metabolite, 1-OH-THA and the CYP1A2 content in liver microsomal samples was found. Evidence for a clozapine, theophylline).At present, caffeine is the model drug of choice for role of CYP1A2 in tacrine metabolism has also emerged from two recent in vivo studies showing an approximately measuring CYP1A2 activity. However, caffeine may not be the ideal probe drug for assessing CYP1A2 activity.85% reduction in the apparent oral clearance of tacrine with concomitant fluvoxamine treatment [15,16]. The clinical use of the caffeine test to predict the CYP1A2-mediated metabolism of drugs in the individual Fluvoxamine is a potent inhibitor of CYP1A2, both in vitro [17] and in vivo [18].

NAT2 and CYP1A2 phenotyping with caffeine: head‐to‐head comparison of AFMU vs. AAMU in the urine metabolite ratios

“…As AFMU has been reported to degrade spontaneously to 5‐acetylamino‐6‐amino‐3‐methyluracil (AAMU), other metabolite ratios have been proposed, notably using AAMU after complete conversion of AFMU under basic conditions [9]. However, AFMU is still widely used for determining CYP1A2 and NAT2 activities [10–14]. The influence on phenotyping results of the presumed decomposition of AFMU in urine has not been formally studied.…”

Orally given melatonin may serve as a probe drug for cytochrome P450 1A2 activity in vivo: A pilot study

“…It should also be mentioned that the caffeine CL is not always in accordance with the CL of other CYP1A2 substrates. [39][40][41] This might be due to the complex metabolism of caffeine and the contribution of other enzymes. 42 It might also be due to different physicochemical properties of the compounds.…”

Pharmacogenetics of drug oxidation via cytochrome P450 (CYP) in the populations of Denmark, Faroe Islands and Greenland

“…In 24 healthy CYP2C19/CYP2D6 extensive metabolizers [78] , it was demonstrated that single oral doses of citalopram, paroxetine and fluoxetine in the dose range of 20 -80 mg did not affect the N3-demethylation of caffeine, which is a marker for CYP1A2, whereas one single dose of 50 mg of fluvoxamine blocked this pathway almost completely. Fluvoxamine also inhibited the biotransformation of tacrine and theophylline in vivo via CYP1A2 [79,80] .…”