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Yuichi Sugiyama - One of the best experts on this subject based on the ideXlab platform.
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Potential Cholestatic Activity of Various Therapeutic Agents Assessed by Bile Canalicular Membrane Vesicles Isolated from Rats and Humans
Drug Metabolism and Pharmacokinetics, 2020Co-Authors: Masato Horikawa, Yukio Kato, Charles A Tyson, Yuichi SugiyamaAbstract:Summary: The Active Transport of solutes mediated by the bile salt export pump (BSEP/ABCB11) and multidrug resistance associated protein-2 (MRP2/ABCC2) are thought to involve bile acid-dependent and -independent bile formation, respectively. To evaluate the potential of therapeutic agents as inhibitors of such Transporters on bile canalicular membranes, we examined the inhibition of the Primary Active Transport of typical substrates by 15 drugs, clinically known to cause cholestasis in canalicular membrane vesicles. The inhibition by most of the compounds in rat canalicular membrane vesicles (CMVs) was minimal or observed at much higher concentrations than obtained in clinical situations. However, cloxacillin, cyclosporin A and midecamycin inhibited BSEP, and cyclosporin A and midecamycin inhibited MRP2 with an inhibition constant close to the clinical concentration. By comparing the inhibition potential between rat and human CMVs, the inhibition of BSEP- and MRP2-mediated Transport by midecamycin and cyclosporin A was relatively similar whereas the inhibitory effect on BSEP-mediated Transport by cloxacillin and glibenclamide was more marked in humans than in rats. These results suggest that the majority of cholestasis-inducing drugs have a minimal inhibitory effect on rat BSEP and MRP2 although species differences in inhibitory potential should be considered, especially in the case of BSEP.
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Physicochemical Parameters Responsible for the Affinity of Methotrexate Analogs for Rat Canalicular Multispecific Organic Anion Transporter (cMOAT/MRP2)
Pharmaceutical Research, 2001Co-Authors: Yukio Kato, Masayuki Haramura, Masateru Ohta, Hiroharu Matsuoka, Yuichi SugiyamaAbstract:Purpose . Canalicular multispecific organic anion Transporter (cMOAT/MRP2) is known to exhibit a broad substrate specificity toward amphiphatic organic anions, including methotrexate (MTX). The present study aims to identify the physicochemical properties of MTX derivatives that correlate with recognition specificity by cMOAT/MRP2. Methods . We examined the inhibitory effect of MTX and 24 analogs on the Transport of [^3H]–S–(2,4–dinitrophenyl)glutathione by cMOAT/MRP2. The affinity constants of these compounds were compared with their physicochemical parameters. The Primary Active Transport of several compounds was also confirmed. Results . The affinity constants closely correlated with the octanol/water partition coefficient (clogP), and a linear combination of polar and nonpolar surface areas. The affinity for cMOAT/MRP2 also closely correlated with the molecular weight, which also showed a significant correlation with nonpolar surface area and clogP. Conclusions . Recognition by cMOAT/MRP2 depends on a balance of dynamic surface properties between the polar and nonpolar regions of MTX analogs. The so–called “molecular weight threshold” for the cMOAT/MRP2 affinity of these compounds can be explained by their physicochemical parameters, especially their nonpolar surface areas.
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Primary Active Transport of organic anions on bile canalicular membrane in humans
American Journal of Physiology-gastrointestinal and Liver Physiology, 1999Co-Authors: Kayoko Niinuma, Yukio Kato, Hiroshi Suzuki, Charles A Tyson, Valorie Weizer, Jack E Dabbs, Ritchie Froehlich, Carol E Green, Yuichi SugiyamaAbstract:Biliary excretion of several anionic compounds was examined by assessing their ATP-dependent uptake in bile canalicular membrane vesicles (CMV) prepared from six human liver samples. 2,4-Dinitrophe...
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Primary Active Transport of peptidic endothelin antagonists by rat hepatic canalicular membrane
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Sharif Akhteruzzaman, Yukio Kato, Akihiro Hisaka, Yuichi SugiyamaAbstract:The biliary excretion mechanism of three derivatives of BQ-123, an anionic cyclopentapeptide, was examined using isolated canalicular membrane vesicles (CMVs) from Sprague-Dawley rats. The uptake by CMV of BQ-485, a linear peptide, BQ-518, a cyclic peptide, and compound A, a cyclic peptide with a cationic moiety, was stimulated by ATP. An “overshoot” phenomenon and saturation were observed for the ATP-dependent uptake of these three peptides. The Michaelis-Menten constants ( K m ) for the uptake of BQ-485 and BQ-518 were comparable to the inhibition constants ( K i ) for their inhibitory effects on ATP-dependent [ 3 H]BQ-123 uptake. The uptake of BQ-485 showed the highest value and was inhibited by BQ-123 with a K i that was comparable to the K m for BQ-123 uptake. The ATP-dependent uptake of BQ-123, BQ-485, and BQ-518 was much lower in CMVs from Eisai hyperbilirubinemic rats, a strain having a hereditary defect of the canalicular multispecific organic anion Transporter (cMOAT). These results suggest that both BQ-485 and BQ-518 principally share the cMOAT Transporter with BQ-123. Compound A almost completely inhibited BQ-123 uptake, although its ATP-dependent uptake was much lower than that of the other three peptides. The ATP-dependent uptake of compound A was not very different in Sprague-Dawley rats and Eisai hyperbilirubinemic rats and was not inhibited by S -(2,4-dinitrophenyl)-glutathione, a typical substrate for cMOAT. Thus, although compound A inhibits cMOAT-mediated Transport, its own Transport by cMOAT is minimal and mediated by another Transporter. This low degree of Primary Active Transport by cMOAT may be the principal reason for its relatively longer residence in the circulation.
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Hepatobiliary Transport Governs Overall Elimination of Peptidic Endothelin Antagonists in Rats
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Yukio Kato, Sharif Akhteruzzaman, Akihiro Hisaka, Yuichi SugiyamaAbstract:The overall disposition and hepatobiliary Transport of BQ-123, an anionic cyclopentapeptide, and three analogs were examined in rats in vivo. Total body clearance ( CL total) and biliary excretion clearance ( CL bile, p) exhibited 4- to 8-fold differences between the compounds, with those for BQ-485 and compound A having the highest and lowest values, respectively. The CL bile, p values of BQ-485, BQ-123, and BQ-518 were almost equal to the CL total, suggesting that hepatobiliary Transport is the major elimination pathway for these compounds. Hepatic uptake clearance ( CL uptake, vivo) and biliary excretion clearance ( CL bile, h/ f T), which was defined for the hepatic unbound concentration, were separately determined to examine the hepatic uptake and excretion processes, respectively. Both the CL uptake, vivo and CL bile, h/ f T of BQ-485 were higher than those of BQ-123, whereas the corresponding values for BQ-518 were similar to those for BQ-123. The CL uptake, vivo and CL bile, h/ f T of compound A were, respectively, approximately two thirds and one half those of BQ-123, suggesting that the lower CL bile, pvalue is due to the low efficiency of both the uptake and excretion processes. The CL uptake, vivo of these four peptides in vivo was similar to the extrapolated values based on the carrier-mediated Transport activity previously assessed in vitro in isolated rat hepatocytes. The Primary Active Transport previously assessed in an in vitro study in canalicular membrane vesicles was also highest for BQ-485 and lowest for compound A, similar to CL bile, h/ f T in vivo. Thus, the Transporters on both the sinusoidal and canalicular membranes determine the efficiency of the peptide overall elimination from the circulation.
Yukio Kato - One of the best experts on this subject based on the ideXlab platform.
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Potential Cholestatic Activity of Various Therapeutic Agents Assessed by Bile Canalicular Membrane Vesicles Isolated from Rats and Humans
Drug Metabolism and Pharmacokinetics, 2020Co-Authors: Masato Horikawa, Yukio Kato, Charles A Tyson, Yuichi SugiyamaAbstract:Summary: The Active Transport of solutes mediated by the bile salt export pump (BSEP/ABCB11) and multidrug resistance associated protein-2 (MRP2/ABCC2) are thought to involve bile acid-dependent and -independent bile formation, respectively. To evaluate the potential of therapeutic agents as inhibitors of such Transporters on bile canalicular membranes, we examined the inhibition of the Primary Active Transport of typical substrates by 15 drugs, clinically known to cause cholestasis in canalicular membrane vesicles. The inhibition by most of the compounds in rat canalicular membrane vesicles (CMVs) was minimal or observed at much higher concentrations than obtained in clinical situations. However, cloxacillin, cyclosporin A and midecamycin inhibited BSEP, and cyclosporin A and midecamycin inhibited MRP2 with an inhibition constant close to the clinical concentration. By comparing the inhibition potential between rat and human CMVs, the inhibition of BSEP- and MRP2-mediated Transport by midecamycin and cyclosporin A was relatively similar whereas the inhibitory effect on BSEP-mediated Transport by cloxacillin and glibenclamide was more marked in humans than in rats. These results suggest that the majority of cholestasis-inducing drugs have a minimal inhibitory effect on rat BSEP and MRP2 although species differences in inhibitory potential should be considered, especially in the case of BSEP.
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Physicochemical Parameters Responsible for the Affinity of Methotrexate Analogs for Rat Canalicular Multispecific Organic Anion Transporter (cMOAT/MRP2)
Pharmaceutical Research, 2001Co-Authors: Yukio Kato, Masayuki Haramura, Masateru Ohta, Hiroharu Matsuoka, Yuichi SugiyamaAbstract:Purpose . Canalicular multispecific organic anion Transporter (cMOAT/MRP2) is known to exhibit a broad substrate specificity toward amphiphatic organic anions, including methotrexate (MTX). The present study aims to identify the physicochemical properties of MTX derivatives that correlate with recognition specificity by cMOAT/MRP2. Methods . We examined the inhibitory effect of MTX and 24 analogs on the Transport of [^3H]–S–(2,4–dinitrophenyl)glutathione by cMOAT/MRP2. The affinity constants of these compounds were compared with their physicochemical parameters. The Primary Active Transport of several compounds was also confirmed. Results . The affinity constants closely correlated with the octanol/water partition coefficient (clogP), and a linear combination of polar and nonpolar surface areas. The affinity for cMOAT/MRP2 also closely correlated with the molecular weight, which also showed a significant correlation with nonpolar surface area and clogP. Conclusions . Recognition by cMOAT/MRP2 depends on a balance of dynamic surface properties between the polar and nonpolar regions of MTX analogs. The so–called “molecular weight threshold” for the cMOAT/MRP2 affinity of these compounds can be explained by their physicochemical parameters, especially their nonpolar surface areas.
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Primary Active Transport of organic anions on bile canalicular membrane in humans
American Journal of Physiology-gastrointestinal and Liver Physiology, 1999Co-Authors: Kayoko Niinuma, Yukio Kato, Hiroshi Suzuki, Charles A Tyson, Valorie Weizer, Jack E Dabbs, Ritchie Froehlich, Carol E Green, Yuichi SugiyamaAbstract:Biliary excretion of several anionic compounds was examined by assessing their ATP-dependent uptake in bile canalicular membrane vesicles (CMV) prepared from six human liver samples. 2,4-Dinitrophe...
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Primary Active Transport of peptidic endothelin antagonists by rat hepatic canalicular membrane
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Sharif Akhteruzzaman, Yukio Kato, Akihiro Hisaka, Yuichi SugiyamaAbstract:The biliary excretion mechanism of three derivatives of BQ-123, an anionic cyclopentapeptide, was examined using isolated canalicular membrane vesicles (CMVs) from Sprague-Dawley rats. The uptake by CMV of BQ-485, a linear peptide, BQ-518, a cyclic peptide, and compound A, a cyclic peptide with a cationic moiety, was stimulated by ATP. An “overshoot” phenomenon and saturation were observed for the ATP-dependent uptake of these three peptides. The Michaelis-Menten constants ( K m ) for the uptake of BQ-485 and BQ-518 were comparable to the inhibition constants ( K i ) for their inhibitory effects on ATP-dependent [ 3 H]BQ-123 uptake. The uptake of BQ-485 showed the highest value and was inhibited by BQ-123 with a K i that was comparable to the K m for BQ-123 uptake. The ATP-dependent uptake of BQ-123, BQ-485, and BQ-518 was much lower in CMVs from Eisai hyperbilirubinemic rats, a strain having a hereditary defect of the canalicular multispecific organic anion Transporter (cMOAT). These results suggest that both BQ-485 and BQ-518 principally share the cMOAT Transporter with BQ-123. Compound A almost completely inhibited BQ-123 uptake, although its ATP-dependent uptake was much lower than that of the other three peptides. The ATP-dependent uptake of compound A was not very different in Sprague-Dawley rats and Eisai hyperbilirubinemic rats and was not inhibited by S -(2,4-dinitrophenyl)-glutathione, a typical substrate for cMOAT. Thus, although compound A inhibits cMOAT-mediated Transport, its own Transport by cMOAT is minimal and mediated by another Transporter. This low degree of Primary Active Transport by cMOAT may be the principal reason for its relatively longer residence in the circulation.
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Hepatobiliary Transport Governs Overall Elimination of Peptidic Endothelin Antagonists in Rats
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Yukio Kato, Sharif Akhteruzzaman, Akihiro Hisaka, Yuichi SugiyamaAbstract:The overall disposition and hepatobiliary Transport of BQ-123, an anionic cyclopentapeptide, and three analogs were examined in rats in vivo. Total body clearance ( CL total) and biliary excretion clearance ( CL bile, p) exhibited 4- to 8-fold differences between the compounds, with those for BQ-485 and compound A having the highest and lowest values, respectively. The CL bile, p values of BQ-485, BQ-123, and BQ-518 were almost equal to the CL total, suggesting that hepatobiliary Transport is the major elimination pathway for these compounds. Hepatic uptake clearance ( CL uptake, vivo) and biliary excretion clearance ( CL bile, h/ f T), which was defined for the hepatic unbound concentration, were separately determined to examine the hepatic uptake and excretion processes, respectively. Both the CL uptake, vivo and CL bile, h/ f T of BQ-485 were higher than those of BQ-123, whereas the corresponding values for BQ-518 were similar to those for BQ-123. The CL uptake, vivo and CL bile, h/ f T of compound A were, respectively, approximately two thirds and one half those of BQ-123, suggesting that the lower CL bile, pvalue is due to the low efficiency of both the uptake and excretion processes. The CL uptake, vivo of these four peptides in vivo was similar to the extrapolated values based on the carrier-mediated Transport activity previously assessed in vitro in isolated rat hepatocytes. The Primary Active Transport previously assessed in an in vitro study in canalicular membrane vesicles was also highest for BQ-485 and lowest for compound A, similar to CL bile, h/ f T in vivo. Thus, the Transporters on both the sinusoidal and canalicular membranes determine the efficiency of the peptide overall elimination from the circulation.
Hiroshi Suzuki - One of the best experts on this subject based on the ideXlab platform.
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Primary Active Transport of organic anions on bile canalicular membrane in humans
American Journal of Physiology-gastrointestinal and Liver Physiology, 1999Co-Authors: Kayoko Niinuma, Yukio Kato, Hiroshi Suzuki, Charles A Tyson, Valorie Weizer, Jack E Dabbs, Ritchie Froehlich, Carol E Green, Yuichi SugiyamaAbstract:Biliary excretion of several anionic compounds was examined by assessing their ATP-dependent uptake in bile canalicular membrane vesicles (CMV) prepared from six human liver samples. 2,4-Dinitrophe...
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Biliary Excretion Mechanism of CPT-11 and Its Metabolites in Humans: Involvement of Primary Active Transporters
Cancer Research, 1998Co-Authors: Yukio Kato, Kayoko Niinuma, Hiroshi Suzuki, Charles A Tyson, Valorie Weizer, Jack E Dabbs, Ritchie Froehlich, Kaoru Ueda, Carol E GreenAbstract:Abstract After administration of CPT-11, a camptothecin derivative exhibiting a wide spectrum of antitumor activity, dose-limiting gastrointestinal toxicity with great interpatient variability is observed. Because the biliary excretion is a major elimination pathway for CPT-11 and its metabolites [an Active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), and its glucuronide, SN38-Glu], several hypotheses for the toxicity involve biliary excretion. Here, we investigated whether Primary Active Transport is involved in the biliary excretion of anionic forms of CPT-11 and its metabolites in humans using bile canalicular membrane vesicles (cMVs). Uptake of the carboxylate form of CPT-11 and the carboxylate and lactone forms of SN38-Glu by cMVs prepared from five human liver samples was ATP dependent. The concentration dependence of the ATP-dependent uptake of the carboxylate form of CPT-11 and SN38-Glu suggests the involvement of at least two saturable Transport components, both with lower affinity and higher capacity than in rats. The ATP-dependent uptake of the carboxylate form of SN-38 showed a single saturable component but was detectable only in one human cMV sample. Both carboxylate and lactone forms of SN38-Glu uptake also showed a large intersample variability, although the variability was less than that observed for the carboxylate form of SN-38. On the other hand, the carboxylate form of CPT-11 exhibited much less variability. The carboxylate forms of SN38-Glu and SN-38 almost completely inhibited the ATP-dependent uptake of leukotriene C4, a well-known substrate of canalicular multispecific organic anion Transporter, whereas the inhibition by the carboxylate form of CPT-11 was not as marked. Thus, multiple Primary Active Transport systems are responsible for the biliary excretion of CPT-11 and its metabolites, and the major Transport system for CPT-11 differs from that for the other two compounds. A greater degree of inter-cMV variability in the uptake of SN-38 and SN38-Glu may imply that interindividual variability in biliary excretion of these metabolites might contribute to interpatient variability in the toxicity caused by CPT-11.
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BILIARY EXCRETION MECHANISM OF IRINOTECAN CPT-1 1 AND ITS METABOLITES IN HUMANS AND RATS: INVOLVEMENT OF cMOAT and P-gp
Drug Metabolism and Pharmacokinetics, 1998Co-Authors: Yukio Kato, Hiroshi Suzuki, Masato Horikawa, Yuichi SugiyamaAbstract:A frequent limiting side-effect of irinotecan, CPT-11, is its gastrointestinal toxicity (diarrhea) thought to be related to the biliary excretion of CPT-11 and its metabolites. Accordingly, we have investigated their biliary excretion mechanism. Our in vivo pharmacokinetic studies in rats revealed that the biliary excretion clearance of the four anionic forms of CPT-11 and its metabolites ways much lower in Eisai hyperbilirubinemic rats (EHBR) with a genetic deficiency of the hepatic canalicular multispecific organic anion Transporter (cMOAT). Detailed analysis using isolated liver bile canalicular membrane vesicles led to identify the multiplicity of Transport systems. Such multiple Primary Active Transport systems are also responsible for the biliary excretion of CPT-11 and its metabolites in humans, and the major Transport systemforOPT-11 differs fromthat forthe othertwo compounds. Greater degree of inter-CMV variability in the uptake of SN-38 and SN38-Glu may imply that interindividual variability in their biliary excretion might contribute to the interpatient variability in the toxicity caused by CPT-11.
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kinetic analysis of the Primary Active Transport of conjugated metabolites across the bile canalicular membrane comparative study ofs 2 4 dinitrophenyl glutathione and 6 hydroxy 5 7 dimethyl 2 methylamino4 3 pyridylmethyl benzothiazole glucuronide
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Kayoko Niinuma, Yukio Kato, Hiroshi Suzuki, Kazuo Kobayashi, Osamu Takenaka, Toru Horie, Yuichi SugiyamaAbstract:Eisai hyperbilirubinemic rat (EHBR) is a mutant strain with a hereditary defect in canalicular multispecific organic anion Transporter (cMOAT). We examined the uptake and mutual inhibition of S-(2,4-dinitrophenyl)-glutathione (DNP-SG), which is a typical substrate for cMOAT, and 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) glucuronide (E-glu) with canalicular membrane vesicles (CMV) prepared from Sprague-Dawley (SD) and EHBR rats to investigate the multiplicity of the organic anion Transporter. The ATP-dependent uptake by CMV from SD rats had an apparent Km of 17.6 μM for DNP-SG and 5.7 μM for E-glu, whereas the corresponding uptake by CMV from EHBR had an apparent Km of 44.6 μM for E-glu. The effects of E-glu, 4-methylumbelliferone glucuronide (4 MUG), E3040 sulfate (E-sul) and 4-methylumbelliferone sulfate (4 MUS) on the uptake of [3H]DNP-SG were also examined. The uptake of [3H]DNP-SG was inhibited by glucuronides (E-glu and 4 MUG) in a concentration-dependent manner, although it was enhanced by the sulfate conjugates (E-sul and 4 MUS). This enhancement was shown to be caused by an increased DNP-SG affinity for the Transporter. In CMV from SD rats, although ATP-dependent uptake of [3H]DNP-SG was almost completely inhibited by E-glu, that of [14C]E-glu was only reduced to about 30% of controls by DNP-SG. On the other hand, in CMV from EHBR, the ATP-dependent uptake of [14C]E-glu was not inhibited at all by DNP-SG. Kinetic analysis indicated that E-glu inhibited DNP-SG uptake competitively. In conclusion: 1) cMOAT recognizes both DNP-SG and E-glu, and another Transporter present in SD rats is also involved in E-glu Transport along with cMOAT; 2) the latter Transporter is kinetically similar to the E-glu Transporter present in EHBR; 3) E-sul enhances the uptake of DNP-SG by increasing the affinity of glucuronide for the Transporter.
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Recent advances in carrier-mediated hepatic uptake and biliary excretion of xenobiotics
Pharmaceutical Research, 1996Co-Authors: Masayo Yamazaki, Hiroshi Suzuki, Yuichi SugiyamaAbstract:Purpose. Besides renal excretion, hepatic metabolism and biliary excretion are the major pathways involved in the removal of xenobiotics. Recently, for many endogenous and exogenous compounds (including drugs), it has been reported that carrier-mediated Transport contributes to hepatic uptake and/ or biliary excretion. In particular, Primary Active Transport mechanisms have been shown to be responsible for the biliary excretion of anticancer drugs, endogenous bile acids and organic anions including glutathione and glucuronic acid conjugates. Primary Active excretion into bile means the positive removal of xenobiotics from the body, and this elimination process is now designated as “Phase III” (T. Ishikawa, Trends Biochem. Sci., 17, 1992) in the detoxification mechanisms for xenobiotics in addition to Phase I by P-450 and Phase II by conjugation.
Kayoko Niinuma - One of the best experts on this subject based on the ideXlab platform.
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Primary Active Transport of organic anions on bile canalicular membrane in humans
American Journal of Physiology-gastrointestinal and Liver Physiology, 1999Co-Authors: Kayoko Niinuma, Yukio Kato, Hiroshi Suzuki, Charles A Tyson, Valorie Weizer, Jack E Dabbs, Ritchie Froehlich, Carol E Green, Yuichi SugiyamaAbstract:Biliary excretion of several anionic compounds was examined by assessing their ATP-dependent uptake in bile canalicular membrane vesicles (CMV) prepared from six human liver samples. 2,4-Dinitrophe...
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Biliary Excretion Mechanism of CPT-11 and Its Metabolites in Humans: Involvement of Primary Active Transporters
Cancer Research, 1998Co-Authors: Yukio Kato, Kayoko Niinuma, Hiroshi Suzuki, Charles A Tyson, Valorie Weizer, Jack E Dabbs, Ritchie Froehlich, Kaoru Ueda, Carol E GreenAbstract:Abstract After administration of CPT-11, a camptothecin derivative exhibiting a wide spectrum of antitumor activity, dose-limiting gastrointestinal toxicity with great interpatient variability is observed. Because the biliary excretion is a major elimination pathway for CPT-11 and its metabolites [an Active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), and its glucuronide, SN38-Glu], several hypotheses for the toxicity involve biliary excretion. Here, we investigated whether Primary Active Transport is involved in the biliary excretion of anionic forms of CPT-11 and its metabolites in humans using bile canalicular membrane vesicles (cMVs). Uptake of the carboxylate form of CPT-11 and the carboxylate and lactone forms of SN38-Glu by cMVs prepared from five human liver samples was ATP dependent. The concentration dependence of the ATP-dependent uptake of the carboxylate form of CPT-11 and SN38-Glu suggests the involvement of at least two saturable Transport components, both with lower affinity and higher capacity than in rats. The ATP-dependent uptake of the carboxylate form of SN-38 showed a single saturable component but was detectable only in one human cMV sample. Both carboxylate and lactone forms of SN38-Glu uptake also showed a large intersample variability, although the variability was less than that observed for the carboxylate form of SN-38. On the other hand, the carboxylate form of CPT-11 exhibited much less variability. The carboxylate forms of SN38-Glu and SN-38 almost completely inhibited the ATP-dependent uptake of leukotriene C4, a well-known substrate of canalicular multispecific organic anion Transporter, whereas the inhibition by the carboxylate form of CPT-11 was not as marked. Thus, multiple Primary Active Transport systems are responsible for the biliary excretion of CPT-11 and its metabolites, and the major Transport system for CPT-11 differs from that for the other two compounds. A greater degree of inter-cMV variability in the uptake of SN-38 and SN38-Glu may imply that interindividual variability in biliary excretion of these metabolites might contribute to interpatient variability in the toxicity caused by CPT-11.
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kinetic analysis of the Primary Active Transport of conjugated metabolites across the bile canalicular membrane comparative study ofs 2 4 dinitrophenyl glutathione and 6 hydroxy 5 7 dimethyl 2 methylamino4 3 pyridylmethyl benzothiazole glucuronide
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Kayoko Niinuma, Yukio Kato, Hiroshi Suzuki, Kazuo Kobayashi, Osamu Takenaka, Toru Horie, Yuichi SugiyamaAbstract:Eisai hyperbilirubinemic rat (EHBR) is a mutant strain with a hereditary defect in canalicular multispecific organic anion Transporter (cMOAT). We examined the uptake and mutual inhibition of S-(2,4-dinitrophenyl)-glutathione (DNP-SG), which is a typical substrate for cMOAT, and 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) glucuronide (E-glu) with canalicular membrane vesicles (CMV) prepared from Sprague-Dawley (SD) and EHBR rats to investigate the multiplicity of the organic anion Transporter. The ATP-dependent uptake by CMV from SD rats had an apparent Km of 17.6 μM for DNP-SG and 5.7 μM for E-glu, whereas the corresponding uptake by CMV from EHBR had an apparent Km of 44.6 μM for E-glu. The effects of E-glu, 4-methylumbelliferone glucuronide (4 MUG), E3040 sulfate (E-sul) and 4-methylumbelliferone sulfate (4 MUS) on the uptake of [3H]DNP-SG were also examined. The uptake of [3H]DNP-SG was inhibited by glucuronides (E-glu and 4 MUG) in a concentration-dependent manner, although it was enhanced by the sulfate conjugates (E-sul and 4 MUS). This enhancement was shown to be caused by an increased DNP-SG affinity for the Transporter. In CMV from SD rats, although ATP-dependent uptake of [3H]DNP-SG was almost completely inhibited by E-glu, that of [14C]E-glu was only reduced to about 30% of controls by DNP-SG. On the other hand, in CMV from EHBR, the ATP-dependent uptake of [14C]E-glu was not inhibited at all by DNP-SG. Kinetic analysis indicated that E-glu inhibited DNP-SG uptake competitively. In conclusion: 1) cMOAT recognizes both DNP-SG and E-glu, and another Transporter present in SD rats is also involved in E-glu Transport along with cMOAT; 2) the latter Transporter is kinetically similar to the E-glu Transporter present in EHBR; 3) E-sul enhances the uptake of DNP-SG by increasing the affinity of glucuronide for the Transporter.
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Mechanism of the tissue distribution and biliary excretion of the cyclic peptide octreotide.
Journal of Pharmacology and Experimental Therapeutics, 1996Co-Authors: Tadashi Yamada, Kayoko Niinuma, Tetsuya Terasaki, Michel Lemaire, Yuichi SugiyamaAbstract:The hepatobiliary Transport and tissue distribution of the cationic cyclooctapeptide octreotide were studies at steady state after its infusion, at various rates, in rats. After an increase in steady-state plasma concentration, marked decrease in the tissue to plasma concentration ratio was observed only in pancreas, the target organ of octreotide. A marked decrease in the biliary excretion clearance, defined with respect to the concentration in the liver, was also observed, suggesting that a Transport carrier was involved in the biliary excretion. The plasma elimination and biliary excretion profiles of octreotide were determined in Eisai hyperbilirubinemic rats (EHBR), which have an hereditary defect of the Active Transport carrier for organic anions in bile canalicular membranes. Although biliary excretion of octreotide was significantly reduced in EHBR, compared with normal Sprague-Dawley rats, no difference was observed in biliary excretion clearance, defined with respect to the concentration in the liver, between Sprague-Dawley rats and EHBR. On the other hand, the liver to plasma concentration ratio in EHBR fell to half that in Sprague-Dawley rats. These results suggest that the decreased biliary excretion of octreotide in EHBR is due not to reduced biliary excretion ability but to reduced hepatic uptake of octreotide. We studied in vitro Transport using bile canalicular membrane vesicles. A significant increase in the Transport of octreotide by bile canalicular membrane vesicles was observed in the presence of ATP, and the estimated kinetic parameters K(m) and Vmax were 6.5 microM and 370 pmol/min/mg of protein, respectively. Similar ATP-dependent uptake was observed in bile canalicular membrane vesicles prepared from EHBR. We concluded that the biliary excretion of octreotide is by ATP-dependent Primary Active Transport and that the carrier system for octreotide differs from the so-called "canalicular multispecific organic anion Transporter," which is absent in EHBR.
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phase 3 detoxification in the liver biliary excretion of small molecules and peptides by Primary Active Transport mechanisms
Drug Metabolism and Pharmacokinetics, 1995Co-Authors: Yuichi Sugiyama, Yukio Kato, Akihiro Hisaka, Tadashi Yamada, Kayoko Niinuma, Hochul Shin, Masayo Yamazaki, Tetsuya Terasaki, Hiroshi SuzukiAbstract:Recently, for many endogenous and exogenous compounds(including drugs), it has been reported that carrier-mediated Primary Active Transport contributes to biliary excretion. Compounds known to be excreted by this mechanism are anticancer drugs, endogenous bile acids and organic anions including glutathione and glucuronic anid conjugates. Primary Active excretion into bile means the positive removal of xenobiotics from the body, and the elimination process is now designated as “Phase III” (T.Ishikawa, Trends Biochem.Sci., 17, 1992) in the detoxification mechanisms for xenobiotics in addition to Phase I by P-450 and Phase II by conjugation. There exist multiplicities in the biliary excretion mechanisms. Clarification of these multiplicities in Transport is necessary not just from a biochemical point of view, but for our understanding of the physiological adaptability of the living body in terms of the removal (detoxification) of xenobiotics. This may provide a lot of important informations for studying the pharmacokinetics of new drugs. In this presentation, I would like to summarize the latest experimental results on carrier-mediated biliary excretion systems and the multiplicities in the biliary excretion of xenobiotics, including small peptides.
Masayo Yamazaki - One of the best experts on this subject based on the ideXlab platform.
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Primary Active Transport of pravastatin across the liver canalicular membrane in normal and mutant eisai hyperbilirubinemic rats
Biopharmaceutics & Drug Disposition, 1996Co-Authors: Masayo Yamazaki, Kazuo Kobayashi, Yuichi SugiyamaAbstract:We have previously demonstrated that the HMG-CoA reductase inhibitor pravastatin is efficiently taken up by the liver via the 'multispecific anion Transporter' in an Active manner. 3 To further examine the fate of pravastatin within the liver, its biliary excretion was studied in a single-pass liver perfusion system and isolated liver canalicular membrane vesicles (CMVs) using normal (Sprague-Dawley rats ; SDRs) and mutant Eisai hyperbilirubinaemic rats (EHBRs). In the liver perfusion experiments, the outflowing drug concentration reached a steady state at 30min and the extraction ratio was approximately 0.7 in both rat strains. Both the steady state biliary excretion rate and bile flow rate of the EHBR group were 40% of those of SDRS. At steady state, the fraction of unchanged drug in bile was 25-34% in both groups. The concentration ratios of unbound drug in cytosol versus that in sinusoid and of that in bile versus that in cytosol were, respectively, 11 and 87 in SDRs, and 13 and 94 in EHBRs. After correction for the membrane potential (-40 mV in cytosol), the ratios became 49 and 19 in SDR and 58 and 21 in EHBRs, respectively. The finding that all of these values were much larger than unity suggested that Active Transport occurred from liver to bile, as well as from plasma to liver, in both rat strains. Furthermore, ATP-dependent uptake of pravastatin was clearly observed in CMVs prepared from EHBRs as well as SDRs, whereas the stimulation by ATP of DNP-SG Transport in CMVs was observed only in SDRs. It was concluded that pravastatin is excreted into bile in high concentrations and a Primary Active Transport mechanism which is maintained in EHBRs contributes to the biliary excretion of this drug.
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Recent advances in carrier-mediated hepatic uptake and biliary excretion of xenobiotics
Pharmaceutical Research, 1996Co-Authors: Masayo Yamazaki, Hiroshi Suzuki, Yuichi SugiyamaAbstract:Purpose. Besides renal excretion, hepatic metabolism and biliary excretion are the major pathways involved in the removal of xenobiotics. Recently, for many endogenous and exogenous compounds (including drugs), it has been reported that carrier-mediated Transport contributes to hepatic uptake and/ or biliary excretion. In particular, Primary Active Transport mechanisms have been shown to be responsible for the biliary excretion of anticancer drugs, endogenous bile acids and organic anions including glutathione and glucuronic acid conjugates. Primary Active excretion into bile means the positive removal of xenobiotics from the body, and this elimination process is now designated as “Phase III” (T. Ishikawa, Trends Biochem. Sci., 17, 1992) in the detoxification mechanisms for xenobiotics in addition to Phase I by P-450 and Phase II by conjugation.
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Recent Advances in Carrier-mediated Hepatic Uptake and Biliary Excretion of Xenobiotics
Pharmaceutical Research, 1996Co-Authors: Masayo Yamazaki, Hiroshi Suzuki, Yuichi SugiyamaAbstract:Purpose . Besides renal excretion, hepatic metabolism and biliary excretion are the major pathways involved in the removal of xenobiotics. Recently, for many endogenous and exogenous compounds (including drugs), it has been reported that carrier-mediated Transport contributes to hepatic uptake and/ or biliary excretion. In particular, Primary Active Transport mechanisms have been shown to be responsible for the biliary excretion of anticancer drugs, endogenous bile acids and organic anions including glutathione and glucuronic acid conjugates. Primary Active excretion into bile means the positive removal of xenobiotics from the body, and this elimination process is now designated as “Phase III” (T. Ishikawa, Trends Biochem. Sci., 17, 1992) in the detoxification mechanisms for xenobiotics in addition to Phase I by P-450 and Phase II by conjugation. Methods . The Transporters, which have been called P-glycoprotein (MDR), multidrug resistance related protein (MRP) and GS-X pump and which are believed to be involved in the Primary Active pumping of xenobiotics from the cells, are now known as the ATP-binding cassette (ABC) Transporters. In this review, we first describe the HMG-CoA reductase inhibitor, pravastatin, as a typical case of a carrier-mediated Active Transport system that contributes to the liver-specific distribution in the body. Results . Regarding biliary excretion, we have summarized recent results suggesting the possible contribution of the ABC Transporters to the biliary excretion of xenobiotics. We also focus on the multiplicities in both hepatic uptake and biliary excretion mechanisms. Analyzing these multiplicities in Transport is necessary not only from a biochemical point of view, but also for our understanding of the physiological adaptability of the living body in terms of the removal (detoxification) of xenobiotics. Conclusions . Clarification of these Transport mechanism may provide important information for studying the pharmacokinetics of new therapeutic drugs and furthermore, leads to the development of the drug delivery systems.
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Kinetic Analysis of Hepatobiliary Transport of Drugs : Importance of Carrier-mediated Transport
Yakugaku Zasshi-journal of The Pharmaceutical Society of Japan, 1995Co-Authors: Masayo Yamazaki, Hiroshi Suzuki, Ryuichiro Nishigaki, Yuichi SugiyamaAbstract:The liver is the major organ involved in the metabolism and elimination of xenobiotics. Evaluating accurately hepatic clearance is very important for predicting the pharmacological effect and/or side-effects of drugs, as well as changes in drug disposition during disease. Recently, for many endogenous and exogenous compounds (including drugs), it has been reported that carrier-mediated Transport contributes to hepatic uptake and/or biliary excretion. In particular, Primary Active Transport mechanisms have been shown to be responsible for the biliary excretion of anticancer drugs, endogenous bile acids and organic anions including glutathione and glucuronic acid conjugates. We have found that a rate-limiting step for several drugs in terms of the hepatic clearance was the membrane Transport process. For these drugs, such a saturable Transport process can be one of the major determinants which influence not only hepatic clearance itself but also disposition (in other words, plasma elimination) in the whole body. We reviewed the carrier-mediated Transport mechanisms involved in the hepatic uptake and biliary excretion processes, the multiplicity of Transport systems, and further, the physiological meaning of these complex Transport systems in the body.
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phase 3 detoxification in the liver biliary excretion of small molecules and peptides by Primary Active Transport mechanisms
Drug Metabolism and Pharmacokinetics, 1995Co-Authors: Yuichi Sugiyama, Yukio Kato, Akihiro Hisaka, Tadashi Yamada, Kayoko Niinuma, Hochul Shin, Masayo Yamazaki, Tetsuya Terasaki, Hiroshi SuzukiAbstract:Recently, for many endogenous and exogenous compounds(including drugs), it has been reported that carrier-mediated Primary Active Transport contributes to biliary excretion. Compounds known to be excreted by this mechanism are anticancer drugs, endogenous bile acids and organic anions including glutathione and glucuronic anid conjugates. Primary Active excretion into bile means the positive removal of xenobiotics from the body, and the elimination process is now designated as “Phase III” (T.Ishikawa, Trends Biochem.Sci., 17, 1992) in the detoxification mechanisms for xenobiotics in addition to Phase I by P-450 and Phase II by conjugation. There exist multiplicities in the biliary excretion mechanisms. Clarification of these multiplicities in Transport is necessary not just from a biochemical point of view, but for our understanding of the physiological adaptability of the living body in terms of the removal (detoxification) of xenobiotics. This may provide a lot of important informations for studying the pharmacokinetics of new drugs. In this presentation, I would like to summarize the latest experimental results on carrier-mediated biliary excretion systems and the multiplicities in the biliary excretion of xenobiotics, including small peptides.