Zylber-Katz E, Caraco Y, Granit L, Levy M
Clinical Pharmacology Unit, Hadassah Univeristy Hospital, Jerusalem, Israel.
Clin Pharmacol Ther. 1995 Aug;58(2):198-209. doi: 10.1016/0009-9236(95)90198-1.
Dipyrone is an analgesic, antipyretic, and anti-inflammatory drug. After oral administration it is hydrolyzed to 4-methylaminoantipyrine and further metabolized to 4-aminoantipyrine, 4-formylaminoantipyrine, and 4-acetylaminoantipyrine. This study investigated the disposition of dipyrone metabolites in 12 hospitalized patients with cirrhosis (age, 25 to 65 years) and 27 healthy subjects of two age groups (young, 21 to 40 years; elderly, 73 to 90 years).
Subjects received 1 gm dipyrone orally, and blood samples were drawn and urine collected over 72 hours. Plasma and urine concentrations of the four metabolites were determined by HPLC.
4-Methylaminoantipyrine terminal elimination half-life (t1/2 beta) in patients with cirrhosis was prolonged compared with young and elderly subjects (mean +/- SEM, 10.6 +/- 0.6 versus 3.1 +/- 0.2 and 4.9 +/- 0.6 hours, p < 0.001), and the nonrenal clearance was reduced compared with the young subjects (1.069 +/- 0.243 versus 2.165 +/- 0.154 ml/min/kg, p < 0.005). 4-Formylaminoantipyrine was undetectable in two patients and in the remaining 10 patients, t1/2 was longer than in the young subjects (26.4 +/- 4.3 versus 10.8 +/- 0.7 hour, p < 0.01), whereas the elderly had intermediate values (18.1 +/- 2.8 hours). Clearance for production of 4-formylaminoantipyrine was reduced in the patients with cirrhosis than in the young and elderly subjects (0.109 +/- 0.024 versus 0.363 +/- 0.031 and 0.340 +/- 0.053 ml/min/kg, p < 0.001). The acetylation phenotype was determined to evaluate the pharmacokinetic parameters of 4-aminoantipyrine and 4-acetylaminoantipyrine. Prolongation of the 4-aminoantipyrine t1/2 and decrease in its clearance for production was found for the patients with cirrhosis, both slow and rapid acetylators, compared with the young and elderly subjects (p < 0.01). 4-Acetylaminoantipyrine t1/2 was also prolonged for patients with cirrhosis, slow and rapid acetylators, compared with the young subjects (p < 0.005). In the slow acetylators, clearance for production of 4-acetylaminoantipyrine did not differ between the patients with cirrhosis and the young subjects (p < 0.5); however, a difference was found for the rapid acetylators (p < 0.001).
Our results show that the disposition of 4-methylaminoantipyrine, 4-aminoantipyrine, 4-formylaminoantipyrine, and 4-acetylaminoantipyrine is reduced by chronic liver disease after a single oral dose of dipyrone.
安乃近是一种解热、镇痛和抗炎药物。口服后，它会水解为4-甲基氨基安替比林，并进一步代谢为4-氨基安替比林、4-甲酰氨基安替比林和4-乙酰氨基安替比林。本研究调查了12例肝硬化住院患者（年龄25至65岁）以及两个年龄组的27名健康受试者（年轻组，21至40岁；老年组，73至90岁）体内安乃近代谢产物的处置情况。
受试者口服1克安乃近，并在72小时内采集血样和尿液。通过高效液相色谱法测定四种代谢产物在血浆和尿液中的浓度。
与年轻和老年受试者相比，肝硬化患者体内4-甲基氨基安替比林的终末消除半衰期（t1/2β）延长（平均值±标准误，10.6±0.6小时对3.1±0.2小时和4.9±0.6小时，p<0.001），且非肾清除率低于年轻受试者（1.069±0.243对2.165±0.154毫升/分钟/千克，p<0.005）。在两名患者中未检测到4-甲酰氨基安替比林，其余10名患者的t1/2比年轻受试者更长（26.4±4.3对10.8±0.7小时，p<0.01），而老年受试者的值处于中间水平（18.1±2.8小时）。肝硬化患者体内4-甲酰氨基安替比林的生成清除率低于年轻和老年受试者（0.109±0.024对0.363±0.031和0.340±0.053毫升/分钟/千克，p<0.001）。通过测定乙酰化表型来评估4-氨基安替比林和4-乙酰氨基安替比林的药代动力学参数。与年轻和老年受试者相比，肝硬化患者（包括慢乙酰化者和快乙酰化者）体内4-氨基安替比林的t1/2延长，其生成清除率降低（p<0.01）。与年轻受试者相比，肝硬化患者（包括慢乙酰化者和快乙酰化者）体内4-乙酰氨基安替比林的t1/2也延长（p<0.005）。在慢乙酰化者中，肝硬化患者和年轻受试者体内4-乙酰氨基安替比林的生成清除率无差异（p<0.5）；然而，在快乙酰化者中发现了差异（p<0.001）。
我们的结果表明，单次口服安乃近后，慢性肝病会降低4-甲基氨基安替比林、4-氨基安替比林、4-甲酰氨基安替比林和4-乙酰氨基安替比林的处置。
