Caffeine clearance

Caffeine (3,7-dihyro-l,3,7-trimethyl-lH-purine-2,6-dione) is a natural product from tea, coffee, and other plants, and is present in many beverages and food. It is primarily metabolized in the liver by cytochrome P450 enzymes to give M-demethylated xanthine and few other metabolites (Fig. 2) [2,48 - 50]. About 17 caffeine metabolites have been identified in humans [51]. 

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Spigset O, Hagg S, Soderstrom E, et al. Lack of correlation between fluvoxamine clearance and CYP1A2 activity as measured by systemic caffeine clearance. EurJ Clin Pharmacol 1999 54 946-946. 

Parsons WD, Neims AH. Effect of smoking on caffeine clearance. Clin Pharmacol Ther 1978 24 40-45. 

The interaction between the quinolone antibacterials and CYP1A2 has been studied in some depth for enoxacin and pefloxacin. Both compounds have been shown to inhibit CYPlA2-mediated metabolism of caffeine in vitro (49). This in vitro inhibition translated into a twofold decrease in caffeine clearance by pefloxacin and a sixfold decrease in clearance by enoxacin (50). Because pefloxacin undergoes N-demethylation to norfloxacin (51) and norfloxacin is much more potent as an inhibitor than pefloxacin (50), the observed in vivo interaction seen for pefloxacin may, in part, be due to norfloxacin. Many other quinolone antibacterial agents have been investigated for their interaction with theophylline, and ciprofloxacin has also been shown to have notable inhibitory effects (52). 

The relative safety of caffeine has lead to its widespread use as an in vivo probe for CYP1A2 activity in man. The primary route of caffeine metabolism is via N-demethylation to paraxanthine, theophylline, and theobromine. The major route of caffeine clearance in man is to paraxanthine (57). The N-3-demethylation of caffeine to paraxanthine has been shown to be mediated by CYP1A2 (58). However, paraxanthine is further metabolized to a number of different products, and as a consequence urinary metabolic ratios are often used to describe an individual CYP1A2 phenotype. 

Campbell ME, Speilberg SP, Kalow W. A urinary metabolite ratio that reflects systemic caffeine clearance. Clin Pharmacol Ther 1987 42 157-165. 

In an attempt to further simplify the caffeine phenotyping test, a trait measure based on the plasma or salivary paraxanthine caffeine concentration ratio between three hours and seven hours after administration of the probe has been suggested (56). High linear correlations (>0.89) have been observed between this trait value and caffeine s oral clearance, and if necessary, a predicted caffeine clearance value may be calculated from the ratio (56). Currently, this phenotyping approach appears to be the simplest and most noninvasive means of readily assessing CYP1A2 activity using caffeine as a probe in addition, the method is reproducible and appears to be robust (56), despite the theoretical dependency of the trait value on the urine flow rate (51). 

Experimental investigations have subsequently confirmed these theoretical findings. For example, significant correlations were obtained between Ratio 4 and caffeine s oral clearance (r = 0.66-0.77, p < 0.002) by several different investigators (47,69,70). By contrast, the correlations between Ratios 1 and 2 and caffeine clearance were generally much poorer (47,69,70) other, less common MRs were also found to be poor measures of caffeine clearance (69). Thus, with the exception of Ratio 4, the validity of other urinary MRs would appear to be... 

Nagel RA, Dirix LY, Hayllar KM, et al. Use of quantitative liver function tests— caffeine clearance and galactose elimination capacity—after orthotopic liver transplantation. J Hepatol 1990 10 149-157. 

Denaro CP, Jacob P HI, Benowitz NL. Evaluation of pharmacokinetic methods used to estimate caffeine clearance and comparison with a Bayesian forecasting method. Ther Drug Monit 1998 20 78-87. 

Jost G, Wahllander A, von Mandach U, et al. Overnight salivary caffeine clearance a liver function test suitable for routine use. Hepatology 1987 7 338-344. 

Wahllander A, Mohr S, Paumgartner G. Assessment of hepatic function— comparison of caffeine clearance in serum and saliva during the day and at night. J Hepatol 1990 10 129-137. 

Denaro CP, Wilson M, Jacob P El, et al. Validation of urine caffeine metabolite ratios with use of stable isotope-labeled caffeine clearance. Clin Pharmacol Ther... 

Culm-Merdek KE, von Moltke LL, Harmatz JS, et al. Fluvoxamine impairs singledose caffeine clearance without altering caffeine pharmacodynamics. Br J Clin Pharmacol 2005 60 486-493. 

On Day 10, the mean caffeine clearance [dose/ AUCo-ool was increased by approx. 3-fold in subjects treated with 400 mg Drug XYZ and 5-fold in subjects treated with 1200 mg... 

There is some suggestion that Phase I bio transformations catalyzed by CYP2C are decreased with age/ with modest decreases in clearance of warfarin (CYP2C9) and phenytoin (CYP2C19) reported in older individuals. However/ this is much less well established (17/ 18). Similarly/ Phase I bio transformation by CYP1A2 may be somewhat decreased in older individuals/ and decreased theophylline and caffeine clearances have been reported (19). However/ this too is not well established. 

Lewis, F.W., Rector, W.G. Caffeine clearance in cirrhosis. The value of simplified determinations of liver metabolic capacity. J. Hepatol. 1992 14 157-162... 

McDonagh, J.E., Nathan, V.V., Bonavia, I.C., Moyle, G.R., Tanner, A.R. Caffeine clearance by enzyme multiplied immunoassay technique a simply inexpensive, and useful indicator of liver function. Gut 1991 32 681-684... 

Wittayalertpanya S, Israsena S, Thamaree S, Tongnop-noua P, Komolmit P. Caffeine clearance by two point analysis A measure of liver function in chronic liver disease. Tokai J Exp Clin Med 1996 21 195-201. 

In 5 subjects cimetidine I g daily for 6 days increased the half-life of a single 300-mg dose of caffeine by about 70% and reduced caffeine clearance. In another study, cimetidine 1.2 g daily for 4 days increased the caffeine half-life by 45% in 6 smokers and by 96% in 6 non-smokers. The caffeine clearance was reduced by 31% in the smokers and by 42% in the non-smokers. A further study found that the caffeine half-life was increased by 59% and the clearance decreased by 40% by cimetidine. Conversely, in a further study in children, cimetidine was not found to affect caffeine metabolism as assessed by the caffeine breath test. ... 

Caffeine clearance is reduced by 30 to 60% by mexiletine, resulting in raised serum caffeine levels. Whether this might result in caffeine toxicity is uncertain. Lidocaine, flecainide and tocainide do not appear to affect caffeine clearance. Caffeine does not significantly alter mexiletine levels. 

Single doses of lidocaine 200 mg, flecainide 100 mg and tocainide 500 mg had no effect on caffeine clearance in 7 healthy subjects given a single 366-mg dose of caffeine. ... 

Abemetity DR, Todd EL. Impairment of caffeine clearance by chronic use of low-dose oestrogen-containing oral contracqjtives. EurJ Clin Pharmacol (1985) 28,425-8. 

Oral methoxsalen and S-methoxypsoralen markedly reduce caffeine clearance but the clinical significance of this is uncertain. Topical methoxsalen does not interact with caffeine. 

There is no accumulation of caffeine or its metabolites in the body and less than 2% of caffeine is excreted imchanged in the urine. Some rate-limiting steps in caffeine metabolism, particularly demethy-lation into paraxanthine that is selectively catalyzed by CYP1A2, determine the rate of caffeine clearance and the dose-dependent pharmacokinetics in humans. 

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