局所麻酔薬ropivacaineのα1-酸性糖タンパク結合動態と薬物間相互作用の検討
はじめに 金沢大学医学部附属病院麻酔科蘇生科において, 心拍動下冠動脈バイパス術の周術期に硬膜外麻酔薬としてropivacaineが使用されてきたが, 手術の経過や患者個々によって麻酔効果が変動することが経験されていた. 局所麻酔薬ropivacaineは, 血漿蛋白結合率が94%の塩基性薬物である1). 一般に, 塩基性薬物は血漿α1-酸性糖蛋白質(AGP)と強く結合することが知られている. また, 薬物非結合型分率(fu)は, 薬理効果や副作用発現に関与することから, しばしば治療域の狭い薬物などでは, 重要なパラメータとなっている. すでに, ropivacaineの体内動態は個体間変動...
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| Published in | 医療薬学 Vol. 31; no. 6; pp. 445 - 450 |
|---|---|
| Main Authors | , , , , , |
| Format | Journal Article |
| Language | Japanese |
| Published |
一般社団法人日本医療薬学会
01.01.2005
日本医療薬学会 |
| Online Access | Get full text |
| ISSN | 1346-342X 1882-1499 |
| DOI | 10.5649/jjphcs.31.445 |
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| Abstract | はじめに 金沢大学医学部附属病院麻酔科蘇生科において, 心拍動下冠動脈バイパス術の周術期に硬膜外麻酔薬としてropivacaineが使用されてきたが, 手術の経過や患者個々によって麻酔効果が変動することが経験されていた. 局所麻酔薬ropivacaineは, 血漿蛋白結合率が94%の塩基性薬物である1). 一般に, 塩基性薬物は血漿α1-酸性糖蛋白質(AGP)と強く結合することが知られている. また, 薬物非結合型分率(fu)は, 薬理効果や副作用発現に関与することから, しばしば治療域の狭い薬物などでは, 重要なパラメータとなっている. すでに, ropivacaineの体内動態は個体間変動が大きく, fu値は血漿AGP濃度が同程度にも関わらず大きく異なることが報告されている2,3). 一方, 血漿AGP濃度は炎症や外傷で上昇することや, 手術後3～4日間にピークに達した後, 2～4週間高値を示すことが報告されている4-6). また, 膵臓がん, 肝炎, ネフローゼ症候群では血漿AGP濃度が低下すると報告されている7-9). |
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| AbstractList | はじめに 金沢大学医学部附属病院麻酔科蘇生科において, 心拍動下冠動脈バイパス術の周術期に硬膜外麻酔薬としてropivacaineが使用されてきたが, 手術の経過や患者個々によって麻酔効果が変動することが経験されていた. 局所麻酔薬ropivacaineは, 血漿蛋白結合率が94%の塩基性薬物である1). 一般に, 塩基性薬物は血漿α1-酸性糖蛋白質(AGP)と強く結合することが知られている. また, 薬物非結合型分率(fu)は, 薬理効果や副作用発現に関与することから, しばしば治療域の狭い薬物などでは, 重要なパラメータとなっている. すでに, ropivacaineの体内動態は個体間変動が大きく, fu値は血漿AGP濃度が同程度にも関わらず大きく異なることが報告されている2,3). 一方, 血漿AGP濃度は炎症や外傷で上昇することや, 手術後3～4日間にピークに達した後, 2～4週間高値を示すことが報告されている4-6). また, 膵臓がん, 肝炎, ネフローゼ症候群では血漿AGP濃度が低下すると報告されている7-9). |
| Author | 福和, 千恵 宮本, 謙一 石崎, 純子 下村, 祥子 横川, 弘一 嶋田, 努 |
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| References | 5) K. Shirao, C. Kusano, S. Natsugoe, H. Yoshinaka, T. Fukumoto, T. Aiko, H. Shimazu, Postoperative changes in acute phase protein in patients with esophageal cancer, Nippon Geka Gakkai Zasshi, 93,675-683 (1992). 6) F.O. Holley, K.V. Ponganis, D.R. Stanski, Effects of cardiac surgery with cardiopulmonary bypass on lidocaine disposition, Clin. Pharmacol. Ther., 35,617-626 (1984). 2) C.J. Erichsen, J. Sjovall, H. Kehlet, C. Hedlund, T. Arvidsson, Pharmacokinetics and analgesic effect of ropivacaine during continuous epidural infusion for postoperative pain relief, Anesthesiology, 84,834-842 (1996). 1) A. Lee, D. Fagan, M. Lamont, G.T. Tucker, M. Halldin, D.B. Scott, Disposition kinetics of ropivacaine in humans, Anesth. Analg., 69,736-738 (1989). 20) C.B. Eap, P. Baumann, Isoelectric focusing of alpha-1 acid glycoprotein (orosomucoid) in immobilized pH-gradients with 8 M urea : detection of its desialylated variants using an alkaline phosphatase-linked secondary antibody system, Electrophoresis, 9,650-654 (1988). 4) P.D. Booker, C. Taylor, G. Saba, Perioperative changes in alpha 1-acid glycoprotein concentrations in infants undergoing major surgery, Br. J. Anaesth., 76,365-368 (1996). 9) K.M. Piafsky, 0. Borga, I. Odar-Cederlof, C. Johansson, F. Sjoqvist, Increased plasma protein binding of propranolol and chlorpromazine mediated by diseaseinduced elevations of plasma alpha 1 acid glycoprotein, N. Engl. J. Med., 299, 1435-1439 (1978). 22) D. Wiedemann, B. Muhlnickel, E. Staroske, W. Neumann, W. Rose, Ropivacaine plasma concentrations during 120-hour epidural infusion, Br. J. Anaesth., 85,830-835 (2000). 11) H. Nakamura, I. Yuasa, K. Umetsu, M. Nakagawa, E. Nanba, K. Kimura, The rearrangement of the human alpha (1) -acid glycoprotein/orosomucoid gene : evidence for tandemly triplicated genes consisting of two AGP 1 and one AGP 2, Biochem. Biophys. Res. Commun., 276,779-784 (2000). 7) K. Trautner, E.H. Cooper, S. Haworth, A.M. Ward, An evaluation of serum protein profiles in the long-term surveillance of prostatic cancer, Scand. J. Urol. Nephrol., 14,143-149 (1980). 21) F. Herve, J.C. Duche, J. Barre, M.C. Millot, J.P. Tillement, pH titration curves of the desialylated human alpha 1-acid glycoprotein variants by combined isoelectrofocusing-electrophoresis : utilization in the development of a fractionation method for the protein variants by chromatography on immobilized metal affinity adsorbent, J. Chromatogr., 577, 43-59 (1992). 13) J. Mittermuller, S. Weidinger, Genetic study of orosomucoid by isoelectric focusing and immunoprinting in patients with carcinoma, Electrophoresis, 13,785-786 (1992). 17) C.B. Eap, C. Cuendet, P. Baumann, Binding of dmethadone, 1-methadone, and dl-methadone to proteins in plasma of healthy volunteers : role of the variants of alpha 1-acid glycoprotein, Clin. Pharmacol. Ther., 47,338-346 (1990). 12) J.C. Duche, S. Urien, N. Simon, E. Malaurie, I. Monnet, J. Barre, Expression of the genetic variants of human alpha-l-acid glycoprotein in cancer, Clin. Biochem., 33,197-202 (2000). 14) J.C. Duche, F. Herve, J.P. Tillement, Study of the expression of the genetic variants of human alpha1-acid glycoprotein in healthy subjects using isoelectric focusing and immunoblotting, J. Chromatogr. B Biomed. Sci., 715,103-109 (1998). 10) I. Yuasa, H. Nakamura, L. Henke, J. Henke, M. Nakagawa, Y. Irizawa, K. Umetsu, Characterization of genomic rearrangements of the alpha 1-acid glycoprotein/orosomucoid gene in Ghanaians, J. Hum. Genet., 46,572-578 (2001). 19) T. Ohshima, T. Takayasu, Simultaneous determination of local anesthetics including ester-type anesthetics in human plasma and urine by gas chromatography-mass spectrometry with solid-phase extraction, J. Chromatogr. B Biomed. Sci. Appl., 726,185-194 (1999). 18) M. Engman, P. Neidenstrom, C. Norsten-Hoog, S.J. Wiklund, U. Bondesson, T. Arvidsson, Determination of ropivacaine and [2 H 3] ropivacaine in biological samples by gas chromatography with nitrogenphosphorus detection or mass spectrometry, J. Chromatogr. B Biomed. Sci., Appl. 709, 57-67 (1998). 3) A.G. Burm, R. Stienstra, R.P. Brouwer, B.M. Emanuelsson, J.W. van Kleef, Epidural infusion of ropivacaine for postoperative analgesia after major orthopedic surgery : pharmacokinetic evaluation, Anesthesiology, 93,395-403 (2000). 8) J. Raynes, Variations in the relative proportions of microheterogeneous forms of plasma glycoproteins in pregnancy and disease, Biomed. Pharmacother., 36, 77-86 (1982). 15) F. Herve, E. Gomas, J.C. Duche, J.P. Tillement, Evidence for differences in the binding of drugs to the two main genetic variants of human alpha 1-acid glycoprotein, Br. J. Clin. Pharmacol., 36,241-249 (1993). 16) S. Taheri, L.P. Cogswell 3rd, A. Gent, G.R. Strichartz, Hydrophobic and ionic factors in the binding of local anesthetics to the major variant of human alpha 1-acid glycoprotein, J. Pharmacol. Exp. Ther., 304, 71-80 (2003). |
| References_xml | – reference: 3) A.G. Burm, R. Stienstra, R.P. Brouwer, B.M. Emanuelsson, J.W. van Kleef, Epidural infusion of ropivacaine for postoperative analgesia after major orthopedic surgery : pharmacokinetic evaluation, Anesthesiology, 93,395-403 (2000). – reference: 6) F.O. Holley, K.V. Ponganis, D.R. Stanski, Effects of cardiac surgery with cardiopulmonary bypass on lidocaine disposition, Clin. Pharmacol. Ther., 35,617-626 (1984). – reference: 18) M. Engman, P. Neidenstrom, C. Norsten-Hoog, S.J. Wiklund, U. Bondesson, T. Arvidsson, Determination of ropivacaine and [2 H 3] ropivacaine in biological samples by gas chromatography with nitrogenphosphorus detection or mass spectrometry, J. Chromatogr. B Biomed. Sci., Appl. 709, 57-67 (1998). – reference: 20) C.B. Eap, P. Baumann, Isoelectric focusing of alpha-1 acid glycoprotein (orosomucoid) in immobilized pH-gradients with 8 M urea : detection of its desialylated variants using an alkaline phosphatase-linked secondary antibody system, Electrophoresis, 9,650-654 (1988). – reference: 22) D. Wiedemann, B. Muhlnickel, E. Staroske, W. Neumann, W. Rose, Ropivacaine plasma concentrations during 120-hour epidural infusion, Br. J. Anaesth., 85,830-835 (2000). – reference: 5) K. Shirao, C. Kusano, S. Natsugoe, H. Yoshinaka, T. Fukumoto, T. Aiko, H. Shimazu, Postoperative changes in acute phase protein in patients with esophageal cancer, Nippon Geka Gakkai Zasshi, 93,675-683 (1992). – reference: 9) K.M. Piafsky, 0. Borga, I. Odar-Cederlof, C. Johansson, F. Sjoqvist, Increased plasma protein binding of propranolol and chlorpromazine mediated by diseaseinduced elevations of plasma alpha 1 acid glycoprotein, N. Engl. J. Med., 299, 1435-1439 (1978). – reference: 8) J. Raynes, Variations in the relative proportions of microheterogeneous forms of plasma glycoproteins in pregnancy and disease, Biomed. Pharmacother., 36, 77-86 (1982). – reference: 1) A. Lee, D. Fagan, M. Lamont, G.T. Tucker, M. Halldin, D.B. Scott, Disposition kinetics of ropivacaine in humans, Anesth. Analg., 69,736-738 (1989). – reference: 12) J.C. Duche, S. Urien, N. Simon, E. Malaurie, I. Monnet, J. Barre, Expression of the genetic variants of human alpha-l-acid glycoprotein in cancer, Clin. Biochem., 33,197-202 (2000). – reference: 19) T. Ohshima, T. Takayasu, Simultaneous determination of local anesthetics including ester-type anesthetics in human plasma and urine by gas chromatography-mass spectrometry with solid-phase extraction, J. Chromatogr. B Biomed. Sci. Appl., 726,185-194 (1999). – reference: 15) F. Herve, E. Gomas, J.C. Duche, J.P. Tillement, Evidence for differences in the binding of drugs to the two main genetic variants of human alpha 1-acid glycoprotein, Br. J. Clin. Pharmacol., 36,241-249 (1993). – reference: 10) I. Yuasa, H. Nakamura, L. Henke, J. Henke, M. Nakagawa, Y. Irizawa, K. Umetsu, Characterization of genomic rearrangements of the alpha 1-acid glycoprotein/orosomucoid gene in Ghanaians, J. Hum. Genet., 46,572-578 (2001). – reference: 11) H. Nakamura, I. Yuasa, K. Umetsu, M. Nakagawa, E. Nanba, K. Kimura, The rearrangement of the human alpha (1) -acid glycoprotein/orosomucoid gene : evidence for tandemly triplicated genes consisting of two AGP 1 and one AGP 2, Biochem. Biophys. Res. Commun., 276,779-784 (2000). – reference: 13) J. Mittermuller, S. Weidinger, Genetic study of orosomucoid by isoelectric focusing and immunoprinting in patients with carcinoma, Electrophoresis, 13,785-786 (1992). – reference: 7) K. Trautner, E.H. Cooper, S. Haworth, A.M. Ward, An evaluation of serum protein profiles in the long-term surveillance of prostatic cancer, Scand. J. Urol. Nephrol., 14,143-149 (1980). – reference: 21) F. Herve, J.C. Duche, J. Barre, M.C. Millot, J.P. Tillement, pH titration curves of the desialylated human alpha 1-acid glycoprotein variants by combined isoelectrofocusing-electrophoresis : utilization in the development of a fractionation method for the protein variants by chromatography on immobilized metal affinity adsorbent, J. Chromatogr., 577, 43-59 (1992). – reference: 14) J.C. Duche, F. Herve, J.P. Tillement, Study of the expression of the genetic variants of human alpha1-acid glycoprotein in healthy subjects using isoelectric focusing and immunoblotting, J. Chromatogr. B Biomed. Sci., 715,103-109 (1998). – reference: 2) C.J. Erichsen, J. Sjovall, H. Kehlet, C. Hedlund, T. Arvidsson, Pharmacokinetics and analgesic effect of ropivacaine during continuous epidural infusion for postoperative pain relief, Anesthesiology, 84,834-842 (1996). – reference: 4) P.D. Booker, C. Taylor, G. Saba, Perioperative changes in alpha 1-acid glycoprotein concentrations in infants undergoing major surgery, Br. J. Anaesth., 76,365-368 (1996). – reference: 16) S. Taheri, L.P. Cogswell 3rd, A. Gent, G.R. Strichartz, Hydrophobic and ionic factors in the binding of local anesthetics to the major variant of human alpha 1-acid glycoprotein, J. Pharmacol. Exp. Ther., 304, 71-80 (2003). – reference: 17) C.B. Eap, C. Cuendet, P. Baumann, Binding of dmethadone, 1-methadone, and dl-methadone to proteins in plasma of healthy volunteers : role of the variants of alpha 1-acid glycoprotein, Clin. Pharmacol. Ther., 47,338-346 (1990). |
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| Snippet | はじめに 金沢大学医学部附属病院麻酔科蘇生科において, 心拍動下冠動脈バイパス術の周術期に硬膜外麻酔薬としてropivacaineが使用されてきたが, 手術の経過や患者個々によって麻酔効果が変動することが経験されていた. 局所麻酔薬ropivacaineは, 血漿蛋白結合率が94%の塩基性薬物である1). 一般に,... |
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| StartPage | 445 |
| Title | 局所麻酔薬ropivacaineのα1-酸性糖タンパク結合動態と薬物間相互作用の検討 |
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