Zimm S, Collins J M, O'Neill D, Chabner B A, Poplack D G
Clin Pharmacol Ther. 1983 Dec;34(6):810-7. doi: 10.1038/clpt.1983.254.
Earlier studies suggested that the dose of 6-mercaptopurine (6-MP) can be reduced substantially when the drug is given with allopurinol. We studied the effect of allopurinol on the kinetics of oral and intravenous 6-MP. Studies conducted initially in rhesus monkeys and subsequently in man with 6-MP doses of 100 mg/m2 and 75 mg/m2, demonstrated that allopurinol pretreatment resulted in a nearly 400% increase in peak plasma concentration of oral 6-MP in monkeys (from a mean of 0.54 microM to a mean of 2.1 microM) and a 500% increase in man (0.74 microM to 3.7 microM). Allopurinol pretreatment also led to a 300% increase in plasma AUC in monkeys after oral 6-MP (from a mean of 121 microM/min to a mean of 391 microM/min) and a 500% increase in AUC in man (from a mean of 142 microM/min to a mean of 716 microM/min). In contrast, allopurinol pretreatment had no effect on the kinetics of intravenous 6-MP. This difference was found to be due to inhibition of first-pass metabolism of oral 6-MP as the result of the action of allopurinol on liver or intestinal xanthine oxidase. Our results indicate that, although dose reduction of oral 6-MP given in conjunction with allopurinol is appropriate, it is not necessary when 6-MP is injected intravenously.
早期研究表明，当6-巯基嘌呤（6-MP）与别嘌呤醇合用时，其剂量可大幅降低。我们研究了别嘌呤醇对口服和静脉注射6-MP动力学的影响。最初在恒河猴身上进行的研究，随后在人体中进行，使用的6-MP剂量分别为100mg/m²和75mg/m²，结果表明，别嘌呤醇预处理使恒河猴口服6-MP的血浆峰值浓度增加了近400%（从平均0.54微摩尔/升增至平均2.1微摩尔/升），在人体中增加了500%（从0.74微摩尔/升增至3.7微摩尔/升）。别嘌呤醇预处理还使恒河猴口服6-MP后的血浆AUC增加了300%（从平均121微摩尔/分钟增至平均391微摩尔/分钟），在人体中AUC增加了500%（从平均142微摩尔/分钟增至平均716微摩尔/分钟）。相比之下，别嘌呤醇预处理对静脉注射6-MP的动力学没有影响。发现这种差异是由于别嘌呤醇对肝脏或肠道黄嘌呤氧化酶的作用抑制了口服6-MP的首过代谢。我们的结果表明，虽然与别嘌呤醇合用时口服6-MP的剂量降低是合适的，但静脉注射6-MP时则没有必要。
