Downs T, Padbury J, Blount L, Kashiwai K, Chan K
Department of Obstetrics and Gynecology, Harbor-UCLA Perinatal Research Laboratories, Torrance 90502, USA.
J Soc Gynecol Investig. 1996 Jul-Aug;3(4):185-90.
To investigate fetal-placental cocaine clearance, and to determine the fetal catecholamine and cardiovascular responses to continuous intravenous cocaine infusion in fetal sheep.
Eleven pregnant ewes and their fetuses (127 +/- 2 days' gestation; term 150 days) were chronically instrumented. Fetuses received intravenous cocaine at 0.05, 0.1, or 0.2 mg/kg/minute. Fetal cardiovascular and hematologic measurements were made before and serially for 90 minutes after initiation of the cocaine infusion.
Steady-state fetal plasma cocaine concentrations were observed by 15 minutes of infusion and averaged 136 +/- 11, 318 +/- 65, and 610 +/- 36 ng/mL, respectively, at each dose. Fetal-placental cocaine clearance rate was independent of dose (337 +/- 39 mL/kg/minute), indicating that it is a first-order pharmacokinetic process. Fetal plasma concentration of benzoylecgonine, a principle cocaine metabolite, increased throughout the study to approximately 25% above cocaine levels by 90 minutes. There were significant increases in fetal heart rate (from 169 +/- 11 to 242 +/- 36 beats per minute), mean blood pressure (from 53 +/- 4 to 63 +/- 5 mmHg), and systolic blood pressure (from 68 +/- 2 to 80 +/- 5 mmHg), with a corresponding increase in catecholamine levels seen in the fetuses infused with 0.2 mg/kg/minute. These changes were not seen in the fetuses given lower doses of cocaine.
Fetal-placental clearance of cocaine is a rapid, first-order pharmacokinetic process. During prolonged cocaine exposure, plasma benzoylecgonine concentrations accumulate significantly. Significant catecholamine and cardiovascular changes are seen in fetal sheep with a continuous infusion of cocaine at 0.2 mg/kg/minute or greater.
研究胎儿-胎盘对可卡因的清除情况，并确定胎儿儿茶酚胺及心血管系统对持续静脉输注可卡因的反应。
对11只怀孕母羊及其胎儿（妊娠127±2天；足月为150天）进行长期仪器植入。胎儿以0.05、0.1或0.2毫克/千克/分钟的剂量静脉输注可卡因。在输注可卡因前及开始输注后连续90分钟进行胎儿心血管和血液学测量。
输注15分钟后观察到胎儿血浆可卡因浓度达到稳态，各剂量下平均分别为136±11、318±65和610±36纳克/毫升。胎儿-胎盘可卡因清除率与剂量无关（337±39毫升/千克/分钟），表明这是一个一级药代动力学过程。可卡因的主要代谢产物苯甲酰爱康宁的胎儿血浆浓度在整个研究过程中持续升高，到90分钟时比可卡因水平高出约25%。胎儿心率（从169±11次/分钟增加到242±36次/分钟）、平均血压（从53±4毫米汞柱增加到63±5毫米汞柱）和收缩压（从68±2毫米汞柱增加到80±5毫米汞柱）显著升高，在以0.2毫克/千克/分钟剂量输注可卡因的胎儿中观察到儿茶酚胺水平相应升高。低剂量可卡因的胎儿未出现这些变化。
胎儿-胎盘对可卡因的清除是一个快速的一级药代动力学过程。在长时间接触可卡因期间，血浆苯甲酰爱康宁浓度会显著累积。持续以0.2毫克/千克/分钟或更高剂量输注可卡因时，胎儿绵羊会出现显著的儿茶酚胺和心血管变化。
