Lee C A, Lillibridge J H, Nelson S D, Slattery J T
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, USA.
J Pharmacol Exp Ther. 1996 Apr;277(1):287-91.
Metabolism of acetaminophen (APAP) to its reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is mediated by cytochrome P450. A pharmacokinetic study was conducted to quantitate changes in the formation clearance (Cl(f)) of NAPQI to assess in vivo the activation and inhibition of NAPQI formation by methylxanthines. Cl(f) of NAPQI was unaltered by methylxanthine administration in saline-pretreated rats. In phenobarbital-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 +/- 1.1 1 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 caffeine demonstrates that P450 activation by caffeine can occur in vivo, as we observed previously in microsomes. The same dose of APAP and methylxanthines also was administered to rats induced with methylcholanthrene. The co-administration of either a single dose of caffeine or theophylline diminished the Cl(f) of NAPQI by 86% (P = .01) and 52% (P = .03), respectively. These in vivo results agree with our previous studies of the effects of the methylxanthines on the formation of NAPQI in rat liver microsomes.
对乙酰氨基酚（APAP）代谢生成其活性代谢产物N - 乙酰 - 对苯醌亚胺（NAPQI）是由细胞色素P450介导的。进行了一项药代动力学研究，以定量NAPQI生成清除率（Cl(f)）的变化，从而在体内评估甲基黄嘌呤对NAPQI生成的激活和抑制作用。在生理盐水预处理的大鼠中，给予甲基黄嘌呤后，NAPQI的Cl(f)未发生改变。在接受无毒剂量APAP（100 mg/kg静脉注射）的苯巴比妥诱导的大鼠中，与APAP同时腹腔注射单剂量咖啡因（100 mg/kg）可使NAPQI生成的Cl(f)从0.58±0.47增加至2.08±1.11 ml/min/kg（P = 0.01）。与咖啡因不同，茶碱（93 mg/kg腹腔注射）对苯巴比妥诱导的大鼠中NAPQI的Cl(f)没有影响。单剂量咖啡因给药后立即出现的NAPQI的Cl(f)增加表明，咖啡因对P450的激活可在体内发生，正如我们之前在微粒体中所观察到的那样。相同剂量的APAP和甲基黄嘌呤也给予了经甲基胆蒽诱导的大鼠。单剂量咖啡因或茶碱的共同给药分别使NAPQI的Cl(f)降低了86%（P = 0.01）和52%（P = 0.03）。这些体内结果与我们之前关于甲基黄嘌呤对大鼠肝微粒体中NAPQI形成影响的研究一致。
