Caffeine oral clearance

Over 95% of caffeine s plasma clearance can be accounted for by the three N-demethylation pathways, all of which are mediated exclusively by CYP1A2 (45,46). Accordingly, measurement of the in vivo probe s oral clearance is the... 

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... 

Fig. 16.6 Changes in bodyweight-normalized clearance (CL) with bodyweight for nine metabolized drugs (a) midazolam, intravenous, (b) midazolam (oral), (c) caffeine (oral), (d) diclofenac (IV),...

The clearances of both theophylline and caffeine are reduced in oral contraceptive users and half-lives are increased, probably because of inhibition of hepatic metabolism by cytochrome P450 (348). Caution in dosage is advisable. 

In a randomised, crossover study, fluvoxamine 50 mg daily for 4 days and then 1(X) mg daily for a further 8 days was given to 8 healthy subjects, with a single 200-mg oral dose of caffeine before and on day 8 of fluvoxamine use. Fluvoxamine reduced the total clearance of caffeine by about 80% (from 107 to 21 mL/minute) and increased its half-life from 5 to 31 hours. Specifically, the clearance of caffeine by Ni-, N - and ETl-demethylation was decreased. Another study in 30 patients found a positive correlation between plasma fluvoxamine and plasma caffeine levels, suggesting that the interaction is dose-related. A further study found that low, sub-therapeutic doses of fluvoxamine 10 or 20 mg daily were sufficient to markedly inhibit caffeine metabolism. A study in 7 subjects found that fluvoxamine 1(X) mg twice daily for 4 doses signifrcantly increased the maximum levels of a single 250-mg dose of caffeine by 40%, and increased the AUC and half-life of caffeine by 12.7-fold and 10-fold, respectively. However, this did not result in an increase in caffeine-related adverse effects, and none of the subjects felt they were more alert with the combination than with either drug alone. ... 

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 idrocilamide reduces the clearance of caffeine, which can lead to caffeine toxicity. 

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

A study in patients receiving PUVA therapy (methoxsalen either orally, in 4 patients, or topically as a bath in 7 patients, plus UVA) found that die clearance of a single 150-mg dose of caffeine was markedly reduced in the patients given oral methoxsalen but not altered in those given topical methoxsalen. ... 

In 6 healthy subjects oral idrocilamide 600 mg daily for 3 days then 1.2 g for 4 days increased the half-life of a single dose of theophylline 2.5-fold, from 8.5 to 21.6 hours, and reduced the clearance by 67%. This is due to a reduction in the liver metabolism caused by the idrocilamide (see also Caffeine + Idrocilamide , p.ll65). Information is very limited but it indicates that concurrent use should be closely monitored. Anticipate the need to reduce the theophylline dosage with oral idrocilamide. 

In 8 healthy subjects a single 150-mg oral dose of phenylpropanolamine decreased the clearance of theophylline (given as a single 4-mg/kg intravenous dose of aminophylline 1 hour after the phenylpropanolamine) by 50%. Such a large reduction in clearance would be expeeted to result in some increase in serum theophylline levels, but so far no studies of this potentially clinically important interaction seem to have been earried out in patients. Be alert for evidence of toxicity if both drugs are used. More study is needed. See also Pseudoephedrine and related drugs + Caffeine , p.1276. 

In healthy volunteers orally administered theophylline with or without two to seven cups of regular instant coffee during a 24-hour study period, blood levels of theophylline and caffeine were significantly higher in the coffee group. The half-life of theophylline was increased from 6.3 to 8.3 h, and the clearance of theophylline was reduced (Sato et al. 1993). 

A decrease in serum levels and an increase in the clearance rate of caffeine was observed in rats orally administered 1 g/kg daily of a hydroalcoholic extract of evodia, or 25 mg/kg daily of the compound rutaecarpine daily, for 3 days prior to the intravenous administration of 5 mg/kg caffeine, a CYP1A2 substrate (Tsai et al. 2005). 

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