Lockwood G F, Chenery R J, Oldham H G, Standring P, Norman S J
Department of Drug Metabolism and Pharmacokinetics, Smith Kline and French Research Ltd, Welwyn, UK.
Eur J Drug Metab Pharmacokinet. 1988 Jul-Sep;13(3):207-14. doi: 10.1007/BF03189941.
Breath tests have been widely advocated for use as non-invasive probes of mixed function oxidase activity in vivo. A catenary sequence of events begins with demethylation and results in the exhalation of 14CO2. Intermediates in this chain include formaldehyde and formate. In this current study [14C]-antipyrine, [14C]-formaldehyde and [14C]-formate have been administered to rats. The data from these one carbon intermediates lead to the conclusion that demethylation is not the rate-limiting step in the antipyrine breath test in the rat. The resultant 14CO2 exhalation rate time profiles have been used to derive a compartmental pharmacokinetic model for the antipyrine breath test in the rat. The simplest catenary model (Antipyrine----formaldehyde----formate----CO2) did not adequately describe the observed data. A compartment in equilibrium with the central compartment for formate was needed to characterize fully the observed data. The derived compartmental model was able to predict qualitatively the effects of phenobarbitone induction on the antipyrine breath test. The quantitative agreement between the model prediction and the observed data could be improved by incorporating the changes in one carbon metabolism produced by phenobarbitone.
呼吸测试作为体内混合功能氧化酶活性的非侵入性检测方法已得到广泛提倡。一系列相关事件始于去甲基化，最终呼出(^{14}CO_2)。该过程中的中间产物包括甲醛和甲酸。在本研究中，已给大鼠注射了([^{14}C])-安替比林、([^{14}C])-甲醛和([^{14}C])-甲酸。来自这些一碳中间产物的数据得出结论，去甲基化不是大鼠安替比林呼吸测试中的限速步骤。所得到的(^{14}CO_2)呼出率随时间变化的曲线已被用于推导大鼠安替比林呼吸测试的房室药代动力学模型。最简单的链式模型（安替比林→甲醛→甲酸→二氧化碳）不能充分描述所观察到的数据。需要一个与甲酸中央房室处于平衡状态的房室来全面表征所观察到的数据。所推导的房室模型能够定性地预测苯巴比妥诱导对安替比林呼吸测试的影响。通过纳入苯巴比妥引起的一碳代谢变化，可以改善模型预测与所观察到的数据之间的定量一致性。
