Comparison of the chromatographie characteristics of metabolites of tacrine hydrochloride in human serum and urine with those of in vitro metabolic products from hepatic microsomes

Truman, Carol; Ford, J. Gair; Roberts, Clive J.

doi:10.1016/0006-2952(91)90061-9

Cited by 13 publications

(6 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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].…”

Section: Discussionmentioning

confidence: 99%

“…The suboptimal predictiveness of the caffeine based tests could be explained if tacrine itself is not be a perfect ‘probe’ for CYP1A2 activity [47]. The major metabolite of tacrine produced by liver microsomes, 1‐OH tacrine, represents <5% of total tacrine metabolites recovered in urine [5, 35]. This is because 1‐OH tacrine undergoes secondary metabolism in the liver and data obtained in liver microsomes suggest that this secondary metabolism is also catalyzed by CYP1A2 [8, 48].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Fontana¹,

deVries

Woolf

et al. 1998

Brit J Clinical Pharma

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Fontana¹,

deVries

Woolf

et al. 1998

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…Five metabolites were demonstrated in serum and urine of patients with Alz- heimer's disease receiving tacrine (Truman et al 1991), and 4 metabolites (l-hydroxy-tacrine, 2hydroxy-tacrine, 4-hydroxy-tacrine and 7hydroxy-tacrine) were identified following incubation of tacrine with human hepatic microsomes (Madden et al 1993). Characterisation of the variety of monohydroxy metabolites found in humans has not been extensive.…”

Section: Metabolism and Eliminationmentioning

confidence: 99%

Tacrine

Wagstaff¹,

McTavish²

1994

Drugs & Aging

124

View full text Add to dashboard Cite

Tacrine is a centrally acting cholinesterase inhibitor with additional pharmacological activity on monoamine levels and ion channels. It has been postulated that some or all of these additional properties may also be relevant to the mode of action of the drug. There are wide interindividual variations in pharmacological and clinical response to tacrine, possibly related to interindividual variation in bioavailability. Tacrine appears to improve cognitive function and behavioural deficits in a proportion of patients with Alzheimer's disease, at dosages of 80 to 160 mg/day. In the best designed trials, 30 to 51% of evaluable patients showed an improvement of at least 4 points on the cognitive subscale of the Alzheimer's Disease Assessment Scale, versus 16 to 25% of placebo recipients. A similar proportion of tacrine recipients were judged to have improved when global assessment scales were used. There was a significant dose-response relationship up to 160 mg/day. However, large numbers of patients were withdrawn during the trials, many because of tacrine-associated increases in transaminase levels. Elevated liver enzyme levels occurred in about 50% of tacrine recipients (reaching clinical significance in about 25%). Cholinergic symptoms also occurred more often in tacrine recipients than in those receiving placebo. A gradual increase in tacrine dosage, at 6-week intervals, is recommended when initiating therapy, and weekly serum transaminase monitoring is required for 6 weeks after each dosage increase. Despite the limitations implied by the low proportion of responders and high incidence of hepatic adverse effects associated with therapy, tacrine appears to make a measurable difference in both cognitive and behavioural function in a proportion of patients with Alzheimer's disease--a welcome advance in an area previously devoid of acceptable treatment options.

show abstract

“…The distribution of tacrine in the brain is saturable and mediated by organic cation transport systems (Sung et al 2005). In-vitro metabolism studies have demonstrated the importance of CYP1A in the biotransformation of tacrine to 1-, 2-, 4-and 7-hydroxylated metabolites (Madden et al 1995b), and the 1-hydroxylated metabolite of tacrine was identified as a major stable metabolite (Truman et al 1991). When species differences in the formation of NADPH-dependent metabolites were studied, high levels of velnacrine were found in the urine of the rat compared with the dog and man (Pool et al 1997).…”

Section: Introductionmentioning

confidence: 99%

Mechanism for increased bioavailability of tacrine in fasted rats

Sung

Hong

Ahn

et al. 2006

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

The mechanism associated with the increased bioavailability of tacrine as a result of a 24-h period of fasting was examined in rats. The AUC value for tacrine after the fasting was 52% higher compared with normal feeding when 4 mg kg(-1) of tacrine was orally administered, but the value for velnacrine, a hydroxylated metabolite of tacrine, was reduced by 10%. The relative metabolic ratio of tacrine in urinary excretion (Au(tacrine) divided by Au(velnacrine)) was lower in fasted rats compared with normally fed rats. This clearly shows that metabolism of tacrine is reduced with 24-h fasting after oral administration. Altered intestinal permeation in the fasting state was hypothesized, and the transport of tacrine across the rat intestine was studied. When a fasted intestine was mounted in an Ussing chamber, the mucosal-to-serosal permeability of tacrine was increased to double that for a fed rat intestine. To examine the effect of absorption rate on the hepatic metabolism of tacrine, a direct pyloric vein infusion study was carried out. Compared with an infusion of tacrine for 5 min, a slow infusion of tacrine over a period of 30 or 60 min increased the hepatic metabolism of tacrine and decreased its systemic clearance in rats. Collectively, these results suggest that rapid transport across the intestine aids tacrine in avoiding hepatic first-pass metabolism and enhances its bioavailability in fasted rats. From these findings, we conclude that both oral administration before a meal and a reduction in the dose might be recommended in tacrine therapy considering the serious hepatotoxicity of tacrine in clinical use.

show abstract

Comparison of the chromatographie characteristics of metabolites of tacrine hydrochloride in human serum and urine with those of in vitro metabolic products from hepatic microsomes

Cited by 13 publications

References 11 publications

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

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

Tacrine

Mechanism for increased bioavailability of tacrine in fasted rats

Contact Info

Product

Resources

About