Szeto H H, Clapp J F, Desiderio D M, Schiller P W, Grigoriants O O, Soong Y, Wu D, Olariu N, Tseng J L, Becklin R
Department of Pharmacology, Cornell University Medical College, New York, New York, USA.
J Pharmacol Exp Ther. 1998 Jan;284(1):61-5.
Although synthetic opioid peptide analogs have been used extensively to study the functional roles of opioid receptors, little is known about their in vivo disposition. Our goal was to develop novel opioid drugs with limited transfer across the placenta. DALDA (Tyr-D-Arg-Phe-Lys-NH2) is a potent and highly selective mu agonist that is quite polar because of its 3+ charge at physiological pH. It can therefore be expected that the distribution of DALDA across the placenta would be highly restricted. In this study, we determined the pharmacokinetics and placental transfer of DALDA after systemic administration in sheep. DALDA was infused intravenously to four nonpregnant and four pregnant sheep at a dose of 0.6 mg/kg/hr for 4 hr. Steady state plasma levels of DALDA were 5436 +/- 464 ng/ml in nonpregnant sheep and 5214 +/- 661 ng/ml in pregnant sheep. A one-compartment open model provided an excellent fit for nonpregnant and pregnant plasma data. The apparent volume of distribution was estimated to be 45.6 +/- 4.4 and 59.2 +/- 7.9 ml/kg in nonpregnant and pregnant animals, respectively. There was no difference in the elimination half-life of DALDA in nonpregnant (1.4 +/- 0.1 hr) and pregnant (1.7 +/- 0.2 hr) animals, and clearance was also similar in nonpregnant (23.1 +/- 1.7 ml/kg/hr) and pregnant (23.7 +/- 1.3 ml/kg/hr) animals. These data suggest that the distribution of DALDA is restricted to plasma volume and that its disposition is not altered in pregnancy. DALDA was not detected in any of the fetal plasma samples (< 50 ng/ml), indicating that fetal plasma concentration is < 1% of maternal concentration. The highly restricted placental distribution of DALDA suggests that it may be a promising opioid drug for obstetrical use.
尽管合成阿片肽类似物已被广泛用于研究阿片受体的功能作用，但其体内处置情况却鲜为人知。我们的目标是开发出胎盘转运有限的新型阿片类药物。DALDA（酪氨酸-D-精氨酸-苯丙氨酸-赖氨酸-NH2）是一种强效且高度选择性的μ激动剂，由于其在生理pH值下带3 +电荷，因而极性很强。因此，可以预期DALDA在胎盘的分布会受到高度限制。在本研究中，我们测定了绵羊全身给药后DALDA的药代动力学和胎盘转运情况。以0.6 mg/kg/小时的剂量对4只未怀孕和4只怀孕绵羊静脉输注DALDA，持续4小时。未怀孕绵羊中DALDA的稳态血浆水平为5436±464 ng/ml，怀孕绵羊中为5214±661 ng/ml。单室开放模型能很好地拟合未怀孕和怀孕绵羊的血浆数据。未怀孕和怀孕动物中DALDA的表观分布容积估计分别为45.6±4.4和59.2±7.9 ml/kg。未怀孕（1.4±0.1小时）和怀孕（1.7±0.2小时）动物中DALDA的消除半衰期无差异，未怀孕（23.1±1.7 ml/kg/小时）和怀孕（23.7±1.3 ml/kg/小时）动物的清除率也相似。这些数据表明DALDA的分布局限于血浆容积，且其处置在怀孕时未改变。在任何胎儿血浆样本中均未检测到DALDA（<50 ng/ml），表明胎儿血浆浓度<母体浓度的1%。DALDA在胎盘的高度受限分布表明它可能是一种有前景的产科用阿片类药物。
