Effect of Aroclor 1254, phenobarbital, and polycyclic aromatic hydrocarbons on the plasma clearance of caffeine in the rat

A thin‐layer chromatographic method is described for the quantitation of caffeine and its dimethylxanthine metabolites, theophylline, theobromine, and paraxanthine. The method was used to evaluate the effect of polycyclic aromatic hydrocarbons (PCH), polychlorinated biphenyls (Aroclor 1254), or phenobarbital on the pharmacokinetics of caffeine and its dimethylxanthine metabolites. The oral administration of benzo[a] pyrene (BP) or Aroclor 1254 to rats for 3 days markedly increased the plasma clearance of caffeine and its dimethylxanthine metabolites. Similar results on the plasma clearance of caffeine were obtained with benzanthracene, dibenzanthracene, chrysene, or pyrene. Although the elimination of caffeine from plasma was increased in rats treated with phenobarbital for 3 days, it was less effective in this respect than the PCH or Aroclor 1254. In addition, phenobarbital did not significantly affect the rate of elimination of the dimethylxanthine metabolites from rat plasma following an intravenous dose of caffeine. Following the intravenous administration of caffeine to rats pretreated with Aroclor 1254 or BP, there was a marked increase in the appearance of theophylline, theobromine, and paraxanthine in plasma. The time to achieve peak plasma levels of these metabolites was reduced from 6 to 7 hr in control rats to I hr in Aroclor 1254‐treated rats and to less than 3 hr in rats treated with BP. Moreover, the plasma elimination of the dimethylxanthine metabolites formed from caffeine was greatly accelerated after pretreatment with BP or Aroclor 1254. A dose‐response study with BP indicated that as little as 1.0 mglkg of BP administered orally for 3 days markedly increased the plasma clearance of caffeine; however, pretreatment with BP did not affect the absolute bioavailability of caffeine. The area under the caffeine plasma curve after oral administration was identical to the area when the same dose was administered intravenously. The above studies indicate that the plasma clearance of caffeine is markedly increased in rats pretreated with phenobarbital, PCH, or Aroclor 1254 and suggest that the metabolism and pharmacology of caffeine may be considerably altered in human subjects exposed to these substances.