EFFECTS OF CAFFEINE AND THEOPHYLLINE AN ACETAMINOPHEN PHARMACOKINETICS - P450 INHIBITION AND ACTIVATION

Metabolism of acetaminophen (APAP) to its reactive metabolite N-acetyl -p-benzoquinoneimine (NAPQI) is mediated by cytochrome P450. A pharmac okinetic study was conducted to quantitate changes in the formation cl earance (Cl-f) of NAPQI to assess in vivo the activation and inhibitio n of NAPQI formation by methylxanthines. Cl-f of NAPQI was unaltered b y methylxanthine administration in saline-pretreated rats. In phenobar bital-induced rats receiving a nontoxic dose of APAP (100 mg/kg i.v.), a single dose of caffeine (100 mg/kg i.p.) co-administered with APAP increased the Cl-f of NAPQI formation from 0.58 +/- 0.47 to 2.08 +/- 1 .11 ml/min/kg (P = .01). Unlike caffeine, theophylline (93 mg/kg i.p.) had no effect on the Cl-f of NAPQI in phenobarbital-induced rats. The increase in the Cl-f of NAPQI immediately after a single dose of caff eine demonstrates that P450 activation by caffeine can occur in vivo, as we observed previously in microsomes. The same dose of APAP and met hylxanthines also was administered to rats induced with methylcholanth rene. The co-administration of either a single dose of caffeine or the ophylline diminished the Cl-f of NAPQI by 86% (P = .01) and 52% (P = . 03), respectively. Thes in vivo results agree with our previous studie s of the effects of the methylxanthines on the formation of NAPQI in r at liver microsomes.