Ince P, Elliott K, Appleton D R, Moorghen M, Finney K J, Sunter J P, Harris A L, Watson A J
University Divisions of Pathology, University of Newcastle upon Tyne, U.K.
Biochem Pharmacol. 1991 Apr 15;41(8):1217-25. doi: 10.1016/0006-2952(91)90661-n.
The in-vitro pharmacokinetics of vincristine (VCR) in normal rat colonic mucosa were studied. Two complementary approaches were adopted using an explant organ-culture system. Firstly [G-3H]vincristine (3HVCR) accumulation, retention and efflux were characterized under basal conditions and compared with measurements made either under energy-depleted conditions, or in the presence of VRP. Secondly, a histological method--the postmetaphase index (PMI)--was used to compare the sensitivity of explants to VCR in the presence or absence of verapamil (VRP). This latter technique involves the measurement, by counting, of the proportion of mitotic figures escaping from metaphase arrest. The studies yielded the following results: 3HVCR accumulation in colonic mucosa showed no evidence of saturability up to the maximum dose studied (130 nM), at a dose of 52 nM accumulation was enhanced in energy-depleted conditions by a factor of 1.8, and in the presence of VRP (6.6 microM) by a factor of 1.4. In the presence of VRP (6.6 microM) retention of 3HVCR was increased by a factor of 1.3 and efflux was reduced by a factor of 0.8 after 2 hr. VRP (6.6 microM) reduced the PMI of colonic mucosal epithelial cells exposed to 11 nM VCR from 18.8% to 11.4% (i.e. 40% reduction) indicating sensitization of the cells to this property of VCR. These results provide evidence that the sensitivity of normal colonic mucosa to vincristine is, at least in part, regulated by drug transport. Qualitatively our observations resemble those described in multidrug resistance. Given that P-glycoprotein has been demonstrated by several groups in colonic mucosal cells, the results support a normal role for this membrane transport molecule in the protection of intestinal cells from plant alkaloids and other xenobiotic agents ingested in the diet.
研究了长春新碱（VCR）在正常大鼠结肠黏膜中的体外药代动力学。采用外植体器官培养系统采用了两种互补方法。首先，在基础条件下对[G-3H]长春新碱（3HVCR）的积累、保留和流出进行了表征，并与在能量耗尽条件下或存在维拉帕米（VRP）时的测量结果进行了比较。其次，使用一种组织学方法——中期后指数（PMI）——来比较在有或没有维拉帕米（VRP）的情况下外植体对VCR的敏感性。后一种技术涉及通过计数来测量从中期阻滞中逃脱的有丝分裂图像的比例。研究得出以下结果：在高达所研究的最大剂量（130 nM）时，结肠黏膜中3HVCR的积累没有饱和迹象，在52 nM剂量下，能量耗尽条件下积累增加了1.8倍，在存在VRP（6.6 microM）时增加了1.4倍。在存在VRP（6.6 microM）的情况下，2小时后3HVCR的保留增加了1.3倍，流出减少了0.8倍。VRP（6.6 microM）将暴露于11 nM VCR的结肠黏膜上皮细胞的PMI从18.8%降低到11.4%（即降低了40%），表明细胞对VCR的这种特性敏感。这些结果提供了证据，表明正常结肠黏膜对长春新碱的敏感性至少部分受药物转运调节。定性地说，我们的观察结果与多药耐药中描述的结果相似。鉴于几个研究小组已在结肠黏膜细胞中证明了P-糖蛋白，这些结果支持了这种膜转运分子在保护肠道细胞免受饮食中摄入的植物生物碱和其他外源性物质影响方面的正常作用。
