DISPOSITION AND METABOLISM OF CODEINE AFTER SINGLE AND CHRONIC DOSES IN ONE POOR AND 7 EXTENSIVE METABOLIZERS
DISPOSITION AND METABOLISM OF CODEINE AFTER SINGLE AND CHRONIC DOSES IN ONE POOR AND 7 EXTENSIVE METABOLIZERS
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DOI：
10.1111/j.1365-2125.1991.tb05550.x
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发表时间：
1991-04-01
影响因子：
3.4
通讯作者：
BOCHNER, F
中科院分区：
文献类型：
--
作者：
CHEN, ZR;SOMOGYI, AA;BOCHNER, F
1 在 8 名受试者（其中 7 名是右美沙芬的强代谢者和 1 名是右美沙芬的低代谢者）中，研究了单次（30 mg）和长期（30 mg，8 小时，七剂）可待因给药后可待因对吗啡、去甲可待因和可待因-6-葡萄糖醛酸的药代动力学、代谢和部分清除率。 通过高效液相色谱法测定可待因、6-葡萄糖醛酸、吗啡和去甲可待因。2 单剂量给药后，达到最大血浆可待因浓度的时间为 0.97 +/- 0.31 小时（平均值 +/- s.d.），而可待因 6-葡萄糖醛酸为 1.28 +/- 0.49 小时。 可待因-6-葡萄糖醛酸苷的血浆AUC比可待因高15.8+/-4.5倍。 唾液中可待因的 AUC 比血浆中高 3.4 +/- 1.1 倍。 可待因的消除半衰期为 3.2 +/- 0.3 h，可待因-6-葡萄糖醛酸的消除半衰期为 3.2 +/- 0.9 h。3 可待因的肾清除率为 183 +/- 59 ml min-1，与尿液 pH 值呈负相关 (r = 0.81)。 这些数据表明可待因在肾小球处经历过滤、肾小管分泌和被动重吸收。 可待因-6-葡萄糖醛酸苷的肾清除率为 55 +/- 21 ml min-1，与尿液 pH 值无关。 其与人血浆的结合率低于10%。 这些数据表明可待因-6-葡萄糖苷酸在肾小球和肾小管重吸收处经历过滤。 后一个过程不太可能是被动的。4 长期给药后，可待因和 6-葡萄糖醛酸可待因的药代动力学与单剂量药代动力学没有显着差异。5 单次给药后，86.1 +/- 11.4% 的剂量在尿液中回收，其中 59.8 +/- 10.3% 为可待因 6-葡萄糖醛酸，7.1 +/- 1.1% 为总吗啡， 6.9 +/- 2.1% 为总去甲可待因，11.8 +/- 3.9% 为未变化可待因。 长期给药后，这些回收率没有显着差异 (P > 0.05)。6 单剂量给药后，7 个强代谢者对吗啡的部分清除率为 137 +/- 31 ml min-1，而弱代谢者为 8 ml min-1；对于去甲可待因，该值为 103 +/- 33 ml min-1 和 90 ml min-1；对于可待因-6-葡萄糖醛酸苷，该值为 914 +/- 129 ml min-1 和 971 ml min-1；内在清除率为 1568 +/- 103 ml min-1 和 1450 ml min-1。 长期给药不会显着改变这些值（P > 0.05）。 在七种快速代谢者中，吗啡的部分清除率值与去甲可待因的值没有显着差异（P > 0.05）。 7 通过检测吗啡的氧化代谢不良代谢物说明了测量部分清除率的有用性，而血浆中母体化合物的测量并未识别出这种重要的代谢缺陷。 8 可待因代谢不良的人可能不会产生与可待因相关的任何药理作用。
1 The pharmacokinetics, metabolism and partial clearances of codeine to morphine, norcodeine and codeine-6-glucuronide after single (30 mg) and chronic (30 mg 8 h for seven doses) administration of codeine were studied in eight subjects (seven extensive and one poor metabolisher of dextromethorphan). Codeine, codeine-6-glucoronide, morphine and norcodeine were measured by high performance liquid chromatographic assays.2 After the single dose, the time to achieve maximum plasma codeine concentrations was 0.97 +/- 0.31 h (mean +/- s.d.) and for codeine-6-glucuronide it was 1.28 +/- 0.49 h. The plasma AUC of codeine-6-glucuronide was 15.8 +/- 4.5 times higher than that of codeine. The AUC of codeine in saliva was 3.4 +/- 1.1 times higher than that in plasma. The elimination half-life of codeine was 3.2 +/- 0.3 h and that of codeine-6-glucuronide was 3.2 +/- 0.9 h.3 The renal clearance of codeine was 183 +/- 59 ml min-1 and was inversely correlated with urine pH (r = 0.81). These data suggest that codeine undergoes filtration at the glomerulus, tubular secretion and passive reabsorption. The renal clearance of codeine-6-glucuronide was 55 +/- 21 ml min-1, and was not correlated with urine pH. Its binding to human plasma was less than 10%. These data suggest that codeine-6-glucuronide undergoes filtration at the glomerulus and tubular reabsorption. This latter process is unlikely to be passive.4 After chronic dosing, the pharmacokinetics of codeine and codeine-6-glucuronide were not significantly different from the single dose pharmacokinetics.5 After the single dose, 86.1 +/- 11.4% of the dose was recovered in urine, of which 59.8 +/- 10.3% was codeine-6-glucuronide, 7.1 +/- 1.1% was total morphine, 6.9 +/- 2.1% was total norcodeine and 11.8 +/- 3.9% was unchanged codeine. These recoveries were not significantly different (P > 0.05) after chronic administration.6 After the single dose, the partial clearance to morphine was 137 +/- 31 ml min-1 in the seven extensive metabolishers and 8 ml min-1 in the poor metabolisher; to norcodeine the values were 103 +/- 33 ml min-1 and 90 ml min-1; to codeine-6-glucuronide the values were 914 +/- 129 ml min-1 and 971 ml min-1; and intrinsic clearance was 1568 +/- 103 ml min-1 and 1450 ml min-1. These values were not significantly (P > 0.05) altered by chronic administration. In the seven extensive metabolishers the values of partial clearance to morphine were not significantly (P > 0.05) different from those to norcodeine.7 The usefulness of measuring partial clearances was illustrated by the detection of the poor oxidative metabolisher to morphine, whereas the measurement of parent compound in plasma did not identify this important metabolic defect.8 Poor metabolishers of codeine may not derive any of the pharmacological effects associated with codeine.