羟丙基-β-环糊精对药物的包合作用及对体内药物动力学的影响
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摘要
环糊精类是由葡萄糖苷键连结成的环状化合物。由于它们可以将疏水性药物包裹在分子腔内而形成包合物，因此可以改变药物的某些性质，提高药物的水溶解度和生物利用度，提高药物的稳定性等。β—环糊精在所有环糊精中是使用最广泛的一种，但由于其水溶解度低，不适宜于在液体制剂中应用。为了提高环糊精的水溶解性，本文研制了β—环糊精的衍生物2—羟丙基—β—环糊精(简称HPCD)。通过控制环氧丙烷与β—环糊精的反应条件，可以得到取代度分布范围相对较小的HPCD，进一步研究了HPCD的纯化方法。应用冰盐水控制反应温度取代了文献的干冰—丙酮作为冷凝液，使之适合产业化生产。本文还提出了化学法测定HPCD羟丙基取代度的方法，本法具有良好的重现性。~1H—核磁共振、~(13)—核磁共振及质谱分析等结果均表明本品的质量与国外进口品相当。本文还采用相溶解度法测定布洛芬、吲哚美辛、尼莫地平、尼群地平、地高辛、美洛昔康、吡洛昔康、尼卡地平和桂利嗪共9种药物与HPCD形成包合物的稳定性常数。
本文以Ⅱ型糖尿病治疗药物那格列奈作为模型药物，采用研磨法及冷冻干燥法制备了那格列奈—HPCD包合物。X—射线衍射法及差示热分析法表明采用冷冻干燥法得到的是包合物。而采用研磨法得到的包合物溶出度低，认为其包合不完全。在不同的pH介质中，那格列奈的溶解度随着体系中加入的HPCD浓度的升高而增加。采用冷冻干燥法制得的那格列奈HPCD-包合物在0.1mol/L盐酸中的溶出度为原药的五倍。用HPLC-MS-MS方法分析了家兔口服包合物的生物利用度，结果表明，口服包合物的吸收速度和吸收程度都比原药有明显提高。
本文采用离体外翻肠囊法研究了HPCD对地高辛透过大鼠小肠粘模的影响。随着小肠营养液中HPCD浓度的提高，地高辛透过小肠粘膜的量则呈现出下降趋势。试验结果表明环糊精包合物降低了药物透过大鼠小肠粘膜的吸收速度。但是，游离药物与被包合药物之间存在着快速平衡，因此仍有部分药物透过小肠粘膜吸收。
本文分别研究了家兔灌胃和健康志愿者口服地高辛HPCD包合物口服液相对于市售片的生物利用度。虽然50％(W/V)HPCD可以提高地高辛的溶解度达2000倍，但是人体生物利用度实验却表明，口服液除达峰时间明显短于片剂外，
沈阳药科大学博卜学位论文
AUCO、和Cmax均无显著性差异，表明口服液比片剂吸收更快，吸收程度相当。
家兔体内的生物利用度实验显示的结果与人体试验相近。口服液和片剂的
AuCO_t，cmax和Tmax均无显著性差异。由此可见，地高辛口服液与片剂是生物等
效的。口服液可以作为地高辛可供选择的有效剂型之一。
本文利用家兔静脉注射HPCD和地高辛的方法研究了HPCD对地高辛体内
药物动力学的影响。当静注地高辛的剂量为0.1 mg瓜g而静注 HPCD的剂量为分
别为0.01眺g和0.2叭g时，注射后15分钟内血清中地高辛的浓度明显高于不
加HPCD的对照组。而当静注地高辛的剂量为0.05m眺g，而即CD的静注剂量
达到1叭g时，血清中地高辛的浓度在30分钟前明显高于对照组。清除相的地
高辛的血清浓度没有因为注射大剂量的HPCD而发生改变。
本文还研究了一种具有血管扩张作用的药物桂利嗦与HPCD共同注射时的
药物动力学。HPCD可以与桂利嗦形成包合物而提高其溶解度。对桂利嗦三种注
射剂处方，进行了药物动力学研究。当注射桂利嗦溶液中HPCD的含量分别为5
%及20%时，与不含HPCD的对照组相比，桂利嗦的血清药物动力学未发现明
显改变。
本文运用离体的大鼠脉络膜及表达了有机阴离子转运多肤的LLC一PKI细胞
作为模型，研究了HPCD对脉络膜及细胞摄取药物的影响。Rl’- PCR实验表明
oatP3在大鼠脉络膜中大量存在，而oatPI的存在是极低的。组织化学印迹法也
说明了OatP3存在于脉络膜与脑脊液接触的粘膜侧。研究结果表明HPCD对雌二
醇17p一葡萄糖醛酸结合物被脉络膜及oatP3细胞摄取的抑制作用呈现浓度依赖
性。研究还发现HPCD对药物进入细胞的抑制作用是由于药物被包裹在HPCD
分子腔内而不是HPCD作用于细胞膜的缘故，并证明了这种抑制作用没有时间
滞后性。本文也证明了oatP3是脉络膜将药物由脑脊液转运到血液中的主要载
体。
本文采用“H放射性同位素标记法研究了HPcD在大鼠体内的组织分布。体
内3H HPcD采用液体闪烁测定仪来测定其放射性强度。大鼠在静脉注射3HHPcD
后肾脏中的放射性强度在各时间点始终大于血液中强度，而肝脏及脾脏中放射性
强度在给药后30分钟以内小于血液，在90分钟时其放射性强度大于血液中。实
验还表明在注射后30分钟内，脑组织中的放射性强度一直在升高，表明HPCD
沈阳药科大学博七学位论文
可以部分地缓慢穿过血脑屏障。
Cyclodextrins are cyclic oligosaccharides, known for their ability to form inclusion complexes with many lipophilic drugs, thereby changing the physicopharmaceutical properties of these drugs. Complexation may increase aqueous solubility and bioavailability, improve stability, and affect the drug's effects. p-Cyclodextrin, which is the most practically used in the pharmaceutical industry, unfortunately has low water solubility, and is difficult to make liquid formulation. Thus, attempts to improve cyclodextrins by chemical derivatization have been made and among these derivatives 2-hydroxypropyl- -cyclodextrin (HPCD) was suggested as one of the most applicable one for its safety. In this paper, conditions for condensation of p-cyclodextrin with propylene oxide were found which give preparations of hydroxypropyl-p-cyclodextrin with a narrow and symmetrical distribution of the degree of substitution. Furthermore, methods for purification of hydroxypropyl-p-cyclodextrin from the contaminating oligopropylene gly
cols were developed. Ion-exchange method was used to separate the sodium chloride. Ice-salt condenser was used to control the reaction temperature. The degree of substitution was detected using a chemical method. Good reproducibility of the degree of substitution for different batches of HPCD was observed. 1H-NMR ,13C-NMR and MS spectra showed average degree of substitution very similar to the imported one. The stability constants of 9 drugs for forming complexes with HPCD were calculated according to phase solubility diagrams. These drugs include ibuprofen, indomethacin, nimodipine, nitrendipine, digoxin, meloxicam, piroxicam, cinnarizine and nicardipine. Nateglinide, a novel highly physiologic, mealtime glucose regulator recently approved for the treatment of type 2 diabetes mellitus, was used as a model drug for the preparation of HPCD-drug inclusion. The formation of solid nateglinide inclusion complexes has been evaluated by using kneading and freeze-drying methods. X-ray diffraction, and differential s
canning calorimetry indicated that inclusion complexes can be obtained by freeze drying. According to the phase solubility results, drug solubility in different media at various pH was improved by inclusion with HPCD.
The dissolution rate of nateglinide for freeze drying includion was 100% in 0.1 mol/L HC1, whereas the dissolution of nateglinide itself was less than 20%. When nateglinide-HPCD complex was orally administered to rabbits, the absorption rate and extent was enhanced significantly comparing to the nateglinide itself.
The everted sac method was used to test the permeability of inclusion complexes of the HPCD and digoxin through rat intestinal membrane. It has been shown that with the increase of the concentration of HPCD, the fraction of digoxin penetrated through the rat membrane decreased as a result. The result indicated that cyclodextrin inclusion decrease the absorption rate of the drug, however, a quick equilibrium was existed between the free drug and drug in inclusion, so the absorption was only partially inhibited. The pharmacokinetic properties of digoxin after oral administration of its HPCD inclusion complex to rabbits and human volunteers were investigated in comparison with those of commercially available tablets. The aqueous solubility of digoxin was enhanced by HPCD for about 2000 times at HPCD concentration of 50% (w/v). But in human bioavailability study no significant difference was observed in the extent of absorption (AUCo-t) and Cmax between the two formulations. Time to reach peak was significantly earlier for solution than tablets (p<0.01). The pharmacokinetic results from the rabbit study were similar to that of human studies and no significant difference was observed for AUC, Cmax and Tmax. As the bioavailability of both tablets and solution is equivalent it is recommended that HPCD based oral digoxin solution could also be an alternative formulation.
The pharmacokinetic interaction for HPCD to digoxin after HPCD and digoxin intravenous administration to rab
本文以Ⅱ型糖尿病治疗药物那格列奈作为模型药物，采用研磨法及冷冻干燥法制备了那格列奈—HPCD包合物。X—射线衍射法及差示热分析法表明采用冷冻干燥法得到的是包合物。而采用研磨法得到的包合物溶出度低，认为其包合不完全。在不同的pH介质中，那格列奈的溶解度随着体系中加入的HPCD浓度的升高而增加。采用冷冻干燥法制得的那格列奈HPCD-包合物在0.1mol/L盐酸中的溶出度为原药的五倍。用HPLC-MS-MS方法分析了家兔口服包合物的生物利用度，结果表明，口服包合物的吸收速度和吸收程度都比原药有明显提高。
本文采用离体外翻肠囊法研究了HPCD对地高辛透过大鼠小肠粘模的影响。随着小肠营养液中HPCD浓度的提高，地高辛透过小肠粘膜的量则呈现出下降趋势。试验结果表明环糊精包合物降低了药物透过大鼠小肠粘膜的吸收速度。但是，游离药物与被包合药物之间存在着快速平衡，因此仍有部分药物透过小肠粘膜吸收。
本文分别研究了家兔灌胃和健康志愿者口服地高辛HPCD包合物口服液相对于市售片的生物利用度。虽然50％(W/V)HPCD可以提高地高辛的溶解度达2000倍，但是人体生物利用度实验却表明，口服液除达峰时间明显短于片剂外，
沈阳药科大学博卜学位论文
AUCO、和Cmax均无显著性差异，表明口服液比片剂吸收更快，吸收程度相当。
家兔体内的生物利用度实验显示的结果与人体试验相近。口服液和片剂的
AuCO_t，cmax和Tmax均无显著性差异。由此可见，地高辛口服液与片剂是生物等
效的。口服液可以作为地高辛可供选择的有效剂型之一。
本文利用家兔静脉注射HPCD和地高辛的方法研究了HPCD对地高辛体内
药物动力学的影响。当静注地高辛的剂量为0.1 mg瓜g而静注 HPCD的剂量为分
别为0.01眺g和0.2叭g时，注射后15分钟内血清中地高辛的浓度明显高于不
加HPCD的对照组。而当静注地高辛的剂量为0.05m眺g，而即CD的静注剂量
达到1叭g时，血清中地高辛的浓度在30分钟前明显高于对照组。清除相的地
高辛的血清浓度没有因为注射大剂量的HPCD而发生改变。
本文还研究了一种具有血管扩张作用的药物桂利嗦与HPCD共同注射时的
药物动力学。HPCD可以与桂利嗦形成包合物而提高其溶解度。对桂利嗦三种注
射剂处方，进行了药物动力学研究。当注射桂利嗦溶液中HPCD的含量分别为5
%及20%时，与不含HPCD的对照组相比，桂利嗦的血清药物动力学未发现明
显改变。
本文运用离体的大鼠脉络膜及表达了有机阴离子转运多肤的LLC一PKI细胞
作为模型，研究了HPCD对脉络膜及细胞摄取药物的影响。Rl’- PCR实验表明
oatP3在大鼠脉络膜中大量存在，而oatPI的存在是极低的。组织化学印迹法也
说明了OatP3存在于脉络膜与脑脊液接触的粘膜侧。研究结果表明HPCD对雌二
醇17p一葡萄糖醛酸结合物被脉络膜及oatP3细胞摄取的抑制作用呈现浓度依赖
性。研究还发现HPCD对药物进入细胞的抑制作用是由于药物被包裹在HPCD
分子腔内而不是HPCD作用于细胞膜的缘故，并证明了这种抑制作用没有时间
滞后性。本文也证明了oatP3是脉络膜将药物由脑脊液转运到血液中的主要载
体。
本文采用“H放射性同位素标记法研究了HPcD在大鼠体内的组织分布。体
内3H HPcD采用液体闪烁测定仪来测定其放射性强度。大鼠在静脉注射3HHPcD
后肾脏中的放射性强度在各时间点始终大于血液中强度，而肝脏及脾脏中放射性
强度在给药后30分钟以内小于血液，在90分钟时其放射性强度大于血液中。实
验还表明在注射后30分钟内，脑组织中的放射性强度一直在升高，表明HPCD
沈阳药科大学博七学位论文
可以部分地缓慢穿过血脑屏障。
Cyclodextrins are cyclic oligosaccharides, known for their ability to form inclusion complexes with many lipophilic drugs, thereby changing the physicopharmaceutical properties of these drugs. Complexation may increase aqueous solubility and bioavailability, improve stability, and affect the drug's effects. p-Cyclodextrin, which is the most practically used in the pharmaceutical industry, unfortunately has low water solubility, and is difficult to make liquid formulation. Thus, attempts to improve cyclodextrins by chemical derivatization have been made and among these derivatives 2-hydroxypropyl- -cyclodextrin (HPCD) was suggested as one of the most applicable one for its safety. In this paper, conditions for condensation of p-cyclodextrin with propylene oxide were found which give preparations of hydroxypropyl-p-cyclodextrin with a narrow and symmetrical distribution of the degree of substitution. Furthermore, methods for purification of hydroxypropyl-p-cyclodextrin from the contaminating oligopropylene gly
cols were developed. Ion-exchange method was used to separate the sodium chloride. Ice-salt condenser was used to control the reaction temperature. The degree of substitution was detected using a chemical method. Good reproducibility of the degree of substitution for different batches of HPCD was observed. 1H-NMR ,13C-NMR and MS spectra showed average degree of substitution very similar to the imported one. The stability constants of 9 drugs for forming complexes with HPCD were calculated according to phase solubility diagrams. These drugs include ibuprofen, indomethacin, nimodipine, nitrendipine, digoxin, meloxicam, piroxicam, cinnarizine and nicardipine. Nateglinide, a novel highly physiologic, mealtime glucose regulator recently approved for the treatment of type 2 diabetes mellitus, was used as a model drug for the preparation of HPCD-drug inclusion. The formation of solid nateglinide inclusion complexes has been evaluated by using kneading and freeze-drying methods. X-ray diffraction, and differential s
canning calorimetry indicated that inclusion complexes can be obtained by freeze drying. According to the phase solubility results, drug solubility in different media at various pH was improved by inclusion with HPCD.
The dissolution rate of nateglinide for freeze drying includion was 100% in 0.1 mol/L HC1, whereas the dissolution of nateglinide itself was less than 20%. When nateglinide-HPCD complex was orally administered to rabbits, the absorption rate and extent was enhanced significantly comparing to the nateglinide itself.
The everted sac method was used to test the permeability of inclusion complexes of the HPCD and digoxin through rat intestinal membrane. It has been shown that with the increase of the concentration of HPCD, the fraction of digoxin penetrated through the rat membrane decreased as a result. The result indicated that cyclodextrin inclusion decrease the absorption rate of the drug, however, a quick equilibrium was existed between the free drug and drug in inclusion, so the absorption was only partially inhibited. The pharmacokinetic properties of digoxin after oral administration of its HPCD inclusion complex to rabbits and human volunteers were investigated in comparison with those of commercially available tablets. The aqueous solubility of digoxin was enhanced by HPCD for about 2000 times at HPCD concentration of 50% (w/v). But in human bioavailability study no significant difference was observed in the extent of absorption (AUCo-t) and Cmax between the two formulations. Time to reach peak was significantly earlier for solution than tablets (p<0.01). The pharmacokinetic results from the rabbit study were similar to that of human studies and no significant difference was observed for AUC, Cmax and Tmax. As the bioavailability of both tablets and solution is equivalent it is recommended that HPCD based oral digoxin solution could also be an alternative formulation.
The pharmacokinetic interaction for HPCD to digoxin after HPCD and digoxin intravenous administration to rab
引文
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[34] Deijns JM, Bouter KP, Hanefeld M, et al. (1998) Nateglinide(A-4166)contrals glycemia in diet-treated type 2 diabetic patints. Diabetologia. 41(Suppl 1):A230,Abstact.
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[36] Novartis公司的那格列奈治疗糖尿病比瑞格列奈好吗．国外药讯，1999；10：17-19
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[56] 中华人民共和国药典(2000年版)(二部)：217-218．
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[33] Hirschberg Y, Karara AH,Pierri AO,Mcleod JF. (2000) Improved control of mealtime glucose excursions with coadministration of nateglinide and metformin. Diabetes Care. 23:349-353
[34] Deijns JM, Bouter KP, Hanefeld M, et al. (1998) Nateglinide(A-4166)contrals glycemia in diet-treated type 2 diabetic patints. Diabetologia. 41(Suppl 1):A230,Abstact.
[35] Karara AH, Dunning BE,Meload JF. (1999) The effect of food on the oralbioavility and the pharmacodynamic actions of the insulinotropic agent nateglinide in healthy subjects J Clin Pharmacol,39:171-179
[36] Novartis公司的那格列奈治疗糖尿病比瑞格列奈好吗．国外药讯，1999；10：17-19
[37] Leung SS,Padden BE,Munson EJ,Grant DJW. (1998) Hydration and dehydration behavior of aspartame hemihydrate. J Pharm Sci. 87:508-513.
[38] Singh D,Marshall PV, Shields L,York P. (1998) Solid-state characterization of chlodiazepoxide polymorphs. J Pharm Sci. 87:655-662.
[39] Wang J, Zhang RH, Sun SY. (1995) Studies on the polymorphism of nimodipine. Acta Pharm sin (in chinese), 30:443-448.
[40] Sumikawa M, Konguchi Y, Ohgane T, Yasuo I,Takahashi,Satoji. Crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine and methods for preparing them [P]. US Pat: 5488150, 1996-01-30.
[41] 李钢，徐群类，姚杰，苏国强，王昉．(2002)那格列奈的多晶型现象．化工时刊，16：17-18．
[42] Tokumura T, Tsushima Y, Kayano M, Machida Y and Nagai T.(1985) Enhancement of Bioavailability of cinnarizine from its β-cyclodextrin complex on oral administration with DL-Phenylalanine as a competeng agent. J Pharm Sci. 74: 496-497.
[43] Jarvinen T, Jarvinen K, Schwarting N, Stella V. J.(1995) β-cyclodextrin derivateives, SBE4-β-CD and HP-β-CD, Increase the oral Bioavailability of Cinnarizine in beagle dogs. J Pharm Sci. 84:295-299.
[44] Dressman J. B. and Lennerns. (2000) Oral Drug Absorption. Marcel Dekker, Inc. New York.
[45] Nakanishi K., Masada.,Nadai T.,and Miyajima K.,(1989)Effect of the interaction of drug-β-cyclodextrin complex with bile salts on the drug absorption from rat small
intestinal lumen. Chem. Pharm. 37:211-214.
[46] Tokumara T., NanbaM., Tsushima Y., Tatsuishi K., Kayano M., Machida Y., Nagai T. (1986) Enhancement of bioavailability of cinnarizine from its beta-cyclodextrin complex on oral administration with DL-phenylalanine as a competing agent. J Pharm Sci. 75:391-394.
[47] Lisalo K (1977) Clinical Pharmacokinetics of Digoxin. Clinical Pharmacoki. 2:1-16.
[48] Uekama K, Fujinaga T, Hirayama F, Otagiri M, Yamasaki M, Seo K, Hashimoto T, and Tsuruoka M, (1983) Improvement of the oral bioavailability of digitalis glycosides by cyclodextrin complexation. J pharm Sci.72:1338-1341.
[49] 李芳，唐跃年，卜书红，肖斌．(1999)地高辛环糊精包合物制剂及其稳定性．儿科药学杂志，5：20-21．
[50] 袁进，赵树进，唐镜波．(2002)地高辛与充血性心衰的治疗．中国药房，13：561-562
[51] 唐跃年，李芳，卜书红．(1999)地高辛环糊精包合物地制备与鉴定．儿科药学杂志，5：13-15．
[52] 李芳，唐跃年，卜书红，肖斌．(2000)地高辛与β—环糊精在水溶液中的包合作用及包合物制剂的稳定性．中国新药杂志，9：245-248．
[53] 王雪梅，王玉琴，王海莲．(1998)影响地高辛血药浓度的因素．首都医药，5：22-24．
[54] 陆路，张相林，赵洁生．(1998)影响地高辛血药浓度的生物统计因素．中国药房，9：225-226．
[55] USP(24版)：572．
[56] 中华人民共和国药典(2000年版)(二部)：217-218．
[57] Uekama K,Fujinaga T, Hirayama F, Otagiri M, Yamasaki M, Seo K, Hashimoto T, and Tsuruoka M,(1983) Improvement of the oral bioavalability of digitalis glycosides by cyclodextrin complexation. J Pharm Sci.72:1338-1341
[58] Lisalo E.(1977) Clinical pharmacokinetics of digoxin.Clinical Pharmacokinetics of digoxin. Clin. Pharmacoki.2:1-16.
[59] Buansinath M, Ghosh SS, Shukla VK, Chopra KS and Mathur VS (1986) Assessment of bio(in)equivalence of deriphyllin-digoxin in human volunteers. Ⅱ .Evaluation of rabbits as qualitative animal model. Methods Find Exp Clin Pharmacol 8: 303-307.
[60] Dix LP, Bai SA, Anderson DL,Riviere JE. (1985) Pharmacokinetics of digoxin in sheep:limitations of the use of biological half-life for interspecies extrapolation.Am J Vet Res,46:470-472.
[61] Harrison LI,Gibaldi M. (1976) Pharmacokinetics of digoxin in the rat. Drug Metab Dispos,4:88-93.
[62] Frijlink HW, Visser J, Hefting NR,Oosting R, Meijer DK,and Lerk CF.(1990) The pharmacokinetics of beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin in the rat. Pharm Res.7:1248-1252.
[63] Frijlink HW, Franssen EJF, Eissens AC, Oosting R, Lerk CF, Meijer DKF.(1991) The effects of cyclodextrins on the disposition of intravenously injected drugs in the rat. Pharm Res. 8:380-384.
[64] Frijlink HW, Eissens AC, Hefting NR, Poelsra K, Lerk CF, Meijer DKF.(1991) Pharm Res. 8:380-384.
[65] Irie T and Uekama K.(1997)Pharmaceutical applications of cyclodextrins. Ⅲ.Toxicological issues and safety evaluation. J Pharm Sci. 86:147-162.
[66] 孙定人，张石革，梁三江 (2001)国家临床新药集，中国医药科技出版社，230-231．
[67] Tokumura T, Nanba M, Tsushima Y, Tatsuishi K, Kayano M, Machida Y, and Nagai T. (1986) Enhancement of bioavailability of cinnnarizine from its beta-cyclodextrin complex on oral administration with DL-phenylalanine as a competing agent. J Pharm Sci. 75:391-394.
[68] Tokumura T. Tsushima Y, Tatauishi K, and Yayano M.(1987) Enhancement of the oral bioavailability of cinnarizine in oleic acid in beagle dogs. J Pharm Sci 76:286-288.
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[71] Bernards CF.(1994) Effects of (Hydroxypropyl)-β-cyclodextrin on flux of morphine, fentanyl, sufentanil, and alfentanil through the spinal meninges of mokey. J Pharm Sci. 620:622.
[72] 张学敏，王宜强主编．(1999) 靶向新基因的分子克隆策略-理论与方法．军事医学科学出版社．北京．
[73] Sugiyama D., Kusuhara H., Shitara Y., Abe.T., Meier PJ.,Sekine T., Endou H., Suzuki H., Sugiyama Y.(2001) Characterization of the efflux transport of 17beta-dstradiol-D-17beta-glucuronide from the brain across rthe blood-brain barrier. J Pharmcol.Exp.Ther.298:316-322.
[74] Kouzuki H, Suzuki H, Stieger B, Meier P J, Sugiyama T. (2000) Characterization of the transport properties of organic anion transporting polypeptidel (Oatp 1) and Na~+/Taurocholate Cotransporting Polypeptide (Ntcp): Comparative Studies on the inhibitory effect of their possible substrate in hepatocytes and cDNA-Transfected Cos-T cells. J Pharmacol and Exp Ther. 292:505-511.
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