Danbury T C, Eccles M, Ford J, Roberts C J
Department of Pharmacology, University of Bristol, UK.
Eur J Drug Metab Pharmacokinet. 1999 Jan-Mar;24(1):91-6. doi: 10.1007/BF03190016.
The aim was to assess tacrine hydrochloride (THA) as an inhibitor of rat hepatic oxidative enzymes. A model of hepatic microsome oxidative metabolism was established using antipyrine (AP) incubated with NADPH. AP and its metabolites, 3-hydroxymethyl antipyrine (HMA). 4-hydroxy antipyrine (OHA) and norantipyrine (NORA) were measured by high performance liquid chromatography (HPLC). Aliquots of 200, 400 and 600 microg/ml antipyrine were incubated with the microsomal preparation alone, with 20 microg/ml cimetidine or with 40, 80 or 200 microg/ml THA. Cimetidine inhibited HMA production by 35-38% (P<0.001) and OHA production by 49-52% (P<0.001). Incubation with the 3 concentrations of THA inhibited HMA production by 17%, 24% and 41% (P<0.001) and OHA production by 52%, 55% and 79%, respectively (P<0.001). NORA was identifiable when antipyrine was incubated with NADPH alone, but could not be identified after incubation with either cimetidine or THA. This study has shown that THA causes the inhibition of AP metabolism to HMA, OHA and possibly NORA. We suggest THA is an inhibitor of three different hepatic microsomal cytochrome P-450 enzyme sub-families.
目的是评估盐酸他克林（THA）作为大鼠肝脏氧化酶抑制剂的作用。使用与NADPH一起孵育的安替比林（AP）建立了肝微粒体氧化代谢模型。通过高效液相色谱法（HPLC）测定AP及其代谢产物3 - 羟甲基安替比林（HMA）、4 - 羟基安替比林（OHA）和去甲安替比林（NORA）。将200、400和600微克/毫升的安替比林等分试样分别单独与微粒体制剂、与20微克/毫升西咪替丁或与40、80或200微克/毫升的THA一起孵育。西咪替丁使HMA生成量降低35 - 38%（P<0.001），使OHA生成量降低49 - 52%（P<0.001）。与3种浓度的THA孵育分别使HMA生成量降低17%、24%和41%（P<0.001），使OHA生成量分别降低52%、55%和79%（P<0.001）。当安替比林单独与NADPH孵育时可检测到NORA，但与西咪替丁或THA孵育后无法检测到。本研究表明，THA可抑制AP代谢生成HMA、OHA以及可能的NORA。我们认为THA是三种不同的肝微粒体细胞色素P - ⁴⁵⁰酶亚家族的抑制剂。
