Conversion of the prodrug etoposide phosphate to etoposide in gastric juice and bile.
Conversion of the prodrug etoposide phosphate to etoposide in gastric juice and bile.
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DOI：
10.1038/bjc.1997.581
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发表时间：
1997
影响因子：
8.8
通讯作者：
de Vries EG
中科院分区：
文献类型：
--
作者：
de Jong RS;Slijfer EA;Uges DR;Mulder NH;de Vries EG
依托泊苷磷酸是依托泊苷的水溶性前药。预计该前药可用于克服口服依托泊苷的溶解度限制和不稳定的生物利用度。为了研究前药在胃肠道腔内转化为依托泊苷的可能性，我们将磷酸依托泊苷溶解于水中，并与人胃液或人胆汁体外孵育。样品采集时间为150 min，用高效液相色谱法测定依托泊苷的浓度。在胃液孵育过程中，前药转化为依托泊苷的过程可以忽略不计。在pH 7-8与胆汁孵育期间有显著的转化。0.1 mg ml-1前药溶液在pH为8时，60 min后前药转化为乙托苷的百分比为78 +/- 18%（平均+/- S.D.）， 0.5 mg ml-1前药溶液为36 +/- 26%。pH为7时，0.1 mg ml-1和0.5 mg ml-1孵育60 min后，22%的前药转化为依托泊苷，10%转化为依托泊苷。在65℃下加热胆汁过夜或在胆汁中加入乙酸二钠使碱性磷酸盐（AP）失活后，没有发现转化。综上所述，由于胆汁中存在AP，口服给药后，肠腔内可将依托泊苷磷酸转化为依托泊苷。这可能会产生重要的药代动力学后果。
Etoposide phosphate is a water-soluble prodrug of etoposide. It was expected that this prodrug could be used to overcome the solubility limitations and erratic bioavailability of oral etoposide. To investigate the possibility of prodrug conversion to etoposide within the gastrointestinal lumen, etoposide phosphate was dissolved in water and incubated with human gastric juice or human bile in vitro. Samples were collected during 150 min and analysed for etoposide concentration with high-performance liquid chromatography. Conversion of prodrug to etoposide during incubation with gastric juice was negligible. There was significant conversion during incubation with bile at pH 7-8. The percentage of prodrug converted to etoposide at pH 8 after 60 min was 78 +/- 18% (mean +/- S.D.) for a 0.1 mg ml-1 prodrug solution and 36 +/- 26% for 0.5 mg ml-1. At pH 7, after 60 min 22% of prodrug was converted to etoposide when incubated at 0.1 mg ml-1 and 10% at 0.5 mg ml-1. No conversion was found after inactivation of alkaline phosphate (AP) by overnight heating of bile at 65 degrees C or by the addition of disodium edetate to the bile. In conclusion, because of AP in bile, variable conversion of etoposide phosphate to etoposide can be expected within the intestinal lumen after oral administration. This could have important pharmacokinetic consequences.