Caffeine pharmacokinetics

Caffeine pharmacokinetics are nonlinear. For example, when comparing a 500 mg dose to a 250 mg dose, the clearance is reduced and elimination half-life is prolonged with the higher dose (Kaplan et al. 1997). Thus, larger doses prolong the action of the drug. Active metabolites of caffeine are paraxanthine, and to a lesser degree, theobromine, and theophylline. Urinary metabolites are I-methylxanthine, l-methyluric acid, and an acetylated uracil derivative. 

Maish WA, Hampton EM, Whitsett TL, Shepard JD, Lovallo WR. Influence of grapefruit juice on caffeine pharmacokinetics and pharmacodynamics. Pharmacotherapy 1996 16(6) 1046-1052. 

Kamimori GH, Lugo SJ, Penetar DM, Chamberlain AC, Brunhart GE, Brunhart AE, Eddington ND. Dose-dependent caffeine pharmacokinetics during severe sleep deprivation in humans. Int J Clin Pharmacol Ther 1995 32(3) 182-186. 

In 24 healthy volunteers, 12 men and 12 women, the women had significantly different caffeine pharmacokinetics in the presence of ciprofloxacin and fleroxacin compared with the men (132). There were also significant differences between the sexes in the pharmacokinetics of ciprofloxacin and fleroxacin in the presence of caffeine. The differences were in part due to different body weights. 

Spreux-Varoquaux, O. Chapalain, J.P. Cordonnier, P. Advenier, C. Pays, M. Lamine, L. Determination of trimethoprim, sulfamethoxazole and its N4-acetyl metabolite in biological fluids by high-performance liquid chromatography. J.Chromatogr., 1983, 274, 187-199 [LOD 15 ng/mL plasma urine normal phase gradient simultaneous theophylline non-interfering caffeine pharmacokinetics]... 

The clearance of caffeine was about twofold higher and its half-life was reduced by about 50% in patients with epilepsy taking phenytoin, when compared with healthy subjects not taking any medications. In the same study, there were no significant differences in caffeine pharmacokinetics between healthy subjects and patients receiving carbamazepine or sodium valproate. Conversely, carbamazepine was considered to have induced the metabolism of caffeine in 5 children with epilepsy, as assessed by the caffeine breath test. In another study in healthy subjects, there was a reduction in the AUC of carbamazepine when it was given with caffeine, but caffeine had no effect on the pharmacokinetics of sodium valproate. ... 

Table 33.3 Effect of quinolones on caffeine pharmacokinetics in healthy subjects...

Buters, J. T., Tang, B. K., Pineau, T., Gelboin, H. V., Kimura, S., and Gonzalez, F. J. (1996). Role of CYP1A2 in caffeine pharmacokinetics and metabolism studies using mice deficient in CYP1A2. Pharmacogenetics 6, 291-296. 

Gender, exercise, and thermal stress have no effect on caffeine pharmacokinetics in men and women. Cigarette smoking increases the elimination of caffeine, whereas decreases have been observed during late pregnancy or with the use of oral contraceptives and in patients with liver diseases. Drug interactions leading to impaired caffeine elimination are frequently reported. 

Kaplan GB, Greenblatt DJ, Ehrenberg BL, Goddard JE, Cotreau MM, Harmatz JS, Shader RI. (1997). Dose-dependent pharmacokinetics and psychomotor effects of caffeine in humans. J Clin Pharmacol. 37(8) 693-703. 

Beach, C. A., Mays, D. C., Sterman, B. M. and Gerber, N. 1985. Metabolism, distribution, seminal excretion and pharmacokinetics of caffeine in the rabbit. Journal of Pharmacology and Experimental Therapy, 233 18-23. 

CA031 Carillo, J. A. and J. Benitez. Clinically significant pharmacokinetic interactions between dietary caffeine and medications. Clin Pharmacokinetics 2000 39(2) 127-153. 

Knutti R, Rothweiler H, Schlatter C Effect of pregnancy on the pharmacokinetics of caffeine. Eur J Clin Pharmacol 21 121-126, 1981... 

As shown below, theophylline is 1,3-dimethylxanthine theobromine is 3,7-dimethylxanthine and caffeine is 1,3,7-trimethylxanthine. A theophylline preparation commonly used for therapeutic purposes is aminophylline, a theophylline-ethylenediamine complex. A synthetic analog of theophylline (dyphylline) is both less potent and shorter-acting than theophylline. The pharmacokinetics of theophylline are discussed below (see Clinical Use of Methylxanthines). The metabolic products, partially demethylated xanthines (not uric acid), are excreted in the urine. 

Caffeine is not extensively bound to plasma proteins therefore, it readily distributes into saliva with a saliva plasma concentration ratio of total drug between 0.74 and 0.94 (52,53). Not surprisingly, therefore, a close correlation exists between saliva and plasma caffeine levels and derived pharmacokinetic parameters. Accordingly, an alternative approach for estimating caffeine s oral... 

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. 

Cysneiros R, Farkas D, Harmatz JS, et al. Pharmacokinetic and pharmacodynamic interactions between zolpidem and caffeine. Clin Pharmacol Ther 2007 82 54-62. 

Ginsberg G, Hattis D, Russ A, Sonawane B (2004c) Physiologically based pharmacokinetic (PBPK) modeling of caffeine and theophylline in neonates and adults Implications for assessing children s risks from environmental agents. J Toxicol Environ Health A, 67(4) 297-329. 

Pharmacokinetics The methylxanthines are well absorbed orally. Caffeine distributes throughout the body, including the brain. The drugs cross the placenta to the fetus and are secreted into the mother s milk. All the methylxanthines are metabolized in the liver, and the metabolites are then excreted in the urine. 

Plasma caffeine and paraxanthine Descriptive pharmacokinetic parameters (standard parameters including peak concentrations (Cmax), time of Cmax (Tmax), area-under-the-curve (AUC) between time 0 and time t where t = 24 h post dose (AUCo-t), AUC after extrapolation to infinity (AUCo-co), apparent terminal half-life total clearance (CL)) for... 

Table 13 Mean (SD) plasma caffeine and paraxanthine pharmacokinetic variables (ng.h/mL) by treatment.

Lau CE, Wang Y, Falk JL. 1997. Differential reinforcement of low rate performance, pharmacokinetics and pharmacokinetic-pharmacodynamic modeling independent interaction of alprazolam and caffeine. J Pharmacol Exp Ther 281 1013-1029. 

Sullivan, F.M., S.E. Smith, and P.R. McElhatton. 1987. Interpretation of animal experiments as illustrated by studies on caffeine. Pp. 123-130 in Pharmacokinetics in Teratogenesis, Vol 1. Interspecies Comparison and Maternal/embryonic-fetal Drug Transfer, H. Nau, and W.J. Scott, eds. Boca Raton, FL CRC Press. 

Klockowski PM. Effect of venlafaxine on CYPlA2-depen-dent pharmacokinetics and metabolism of caffeine. J Clin Pharmacol 1999 39(3) 252-9. 

Eap CB, Bondolfi G, Zullino D, Bryois C, Fuciec M, Savary L, Jonzier-Perey M, Baumann P. Pharmacokinetic drug interaction potential of risperidone with cytochrome p450 isozymes as assessed by the dextromethorphan, the caffeine, and the mephenytoin test. Ther Drug Monit 2001 23(3) 228-31. 

Influence of other medicinal products which are normally administered concomitantly. Possible pharmacodynamic and pharmacokinetic interactions with other medicinal products or substances like alcohol, caffeine, tobacco, nicotine. 

GC-MS methods provide greater specificity and in many cases sensitivity when compared with more conventional techniques. They offer increased scope for the study of pharmacokinetics and of plasma concentration in relation to biological effect. SIM assay has been applied to the investigation of placental transfer of lipid soluble drugs and their subsequent elimination in the newborn (barbiturates, diphenylhydantoin, caffeine, pethidine and diazepam [122,408] diphenylhydantoin [411] amylobarbitone and 3 -hydroxyamylobarbitone [83,423]). 

Pharmacokinetics. Absorption of xanthines after oral or rectal administration varies with the preparation used. It is generally extensive (> 95%). Caffeine metabolism varies much between individuals (t/ 2-12 h). Xanthines are metabolised (more than 90%) by numerous mixed function oxidase enzymes, and xanthine oxidase. (For further details on theophylline, see Asthma.)... 

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