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Norma Selve - One of the best experts on this subject based on the ideXlab platform.
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complementary and synergistic antinociceptive interaction between the Enantiomers of tramadol
Journal of Pharmacology and Experimental Therapeutics, 1993Co-Authors: Robert B. Raffa, Elmar Friderichs, Wolfgang Reimann, Richard P. Shank, Ellen E. Codd, J. L. Vaught, Henry I. Jacoby, Norma SelveAbstract:The explanation for the co-existence of opioid and nonopioid components of tramadol-induced antinociception appears to be related to the different, but complementary and interactive, pharmacologies of its Enantiomers. The (+) enantiomer had Ki values of only 1.33, 62.4 and 54.0 microM at mu, delta and kappa receptors, respectively. The (-) enantiomer had even lower affinity at the mu and delta sites (Ki = 24.8, 213 and 53.5 microM, respectively. The (+) enantiomer was the most potent inhibitor of serotonin uptake (Ki = 0.53 microM) and the (-) enantiomer was the most potent inhibitor of norepinephrine uptake (Ki = 0.43 microM). Basal serotonin release was preferentially enhanced by the (+) enantiomer and stimulation-evoked norepinephrine release was preferentially enhanced by the (-) enantiomer. The (+) and (-) Enantiomers each independently produced centrally mediated antinociception in the acetylcholine-induced abdominal constriction test (ED50 = 14.1 and 35.0 micrograms i.t., respectively). Racemic tramadol was significantly more potent (P
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Complementary and synergistic antinociceptive interaction between the Enantiomers of tramadol.
The Journal of pharmacology and experimental therapeutics, 1993Co-Authors: Robert B. Raffa, Elmar Friderichs, Wolfgang Reimann, Richard P. Shank, Ellen E. Codd, J. L. Vaught, Henry I. Jacoby, Norma SelveAbstract:The explanation for the co-existence of opioid and nonopioid components of tramadol-induced antinociception appears to be related to the different, but complementary and interactive, pharmacologies of its Enantiomers. The (+) enantiomer had Ki values of only 1.33, 62.4 and 54.0 microM at mu, delta and kappa receptors, respectively. The (-) enantiomer had even lower affinity at the mu and delta sites (Ki = 24.8, 213 and 53.5 microM, respectively. The (+) enantiomer was the most potent inhibitor of serotonin uptake (Ki = 0.53 microM) and the (-) enantiomer was the most potent inhibitor of norepinephrine uptake (Ki = 0.43 microM). Basal serotonin release was preferentially enhanced by the (+) enantiomer and stimulation-evoked norepinephrine release was preferentially enhanced by the (-) enantiomer. The (+) and (-) Enantiomers each independently produced centrally mediated antinociception in the acetylcholine-induced abdominal constriction test (ED50 = 14.1 and 35.0 micrograms i.t., respectively). Racemic tramadol was significantly more potent (P < .05) than the theoretical additive effect of the Enantiomers (antinociceptive synergy). Synergy was also demonstrated (P < .1) in the mouse 55 degrees C hot-plate test (i.p. route) and (P < .05) the rat Randall-Selitto yeast-induced inflammatory nociception model (i.v. and i.p. routes). Critically, the Enantiomers interacted less than synergistically in two side-effects of inhibition of colonic propulsive motility and impairment of rotarod performance. The racemate and the (+) enantiomer were active in a chronic (arthritic) inflammatory pain model. Taken together, these findings provide a rational explanation for the coexistence of dual components to tramadol-induced antinociception and might form the basis for understanding its clinical profile.
S Kawahara - One of the best experts on this subject based on the ideXlab platform.
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Enantiomer-enantiomer interaction of a uricosuric antihypertensive diuretic (DBCA) in renal tubular secretion and stereoselective inhibition by probenecid in the cynomolgus monkey
Xenobiotica, 1993Co-Authors: M. Nakano, Kenji Higaki, S KawaharaAbstract:1. Enantiomer-enantiomer interaction of 5-dimethylsulphamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (DBCA), a uricosuric, diuretic and antihypertensive agent, was studied from the pharmacokinetics of the Enantiomers following intravenous injection of individual Enantiomers and racemate into male cynomolgus monkeys. Also studied was the involvement of the anion transport system in the renal excretion of DBCA by comparison of the pharmacokinetics in probenecid-treated and non-treated animals.2. Separate administration of individual Enantiomers showed higher plasma concentrations of (S)(—)-DBCA than those of the antipode, at an early period after dosing. Both Enantiomers disappeared rapidly from plasma with an elimination half-life (t1/2β) of 0.35–0.38 h. Unbound fractions were 18.9% for the (R)(+)-enantiomer and 10.2% for the (S)(—)-enantiomer. The major portion of both Enantiomers was excreted by 6 h after dosing and 77-78% of the dose was recovered within 48 h, principally as the unchanged d...
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Enantiomer-enantiomer interaction of a uricosuric antihypertensive diuretic (DBCA) in renal tubular secretion and stereoselective inhibition by probenecid in the cynomolgus monkey
Xenobiotica; the fate of foreign compounds in biological systems, 1993Co-Authors: M. Nakano, Kenji Higaki, S KawaharaAbstract:1. Enantiomer-enantiomer interaction of 5-dimethylsulphamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxyl ic acid (DBCA), a uricosuric, diuretic and antihypertensive agent, was studied from the pharmacokinetics of the Enantiomers following intravenous injection of individual Enantiomers and racemate into male cynomolgus monkeys. Also studied was the involvement of the anion transport system in the renal excretion of DBCA by comparison of the pharmacokinetics in probenecid-treated and non-treated animals. 2. Separate administration of individual Enantiomers showed higher plasma concentrations of (S)(-)-DBCA than those of the antipode, at an early period after dosing. Both Enantiomers disappeared rapidly from plasma with an elimination half-life (t1/2 beta) of 0.35-0.38 h. Unbound fractions were 18.9% for the (R)(+)-enantiomer and 10.2% for the (S)(-)-enantiomer. The major portion of both Enantiomers was excreted by 6 h after dosing and 77-78% of the dose was recovered within 48 h, principally as the unchanged drug. Tubular secretion contributed significantly to the renal excretion of DBCA, because tubular secretion clearance values of unbound drug (CLrf,s) were 14- to 29-fold greater than creatinine clearance. 3. The presence of the antipode decreased the tubular secretion clearance (CLrf,s) value of unbound (S)(-)-enantiomer by 30%, and tended to decrease that for the unbound (R)(+)-enantiomer, although not significantly. This indicates the occurrence of enantiomer-enantiomer interaction in the process of renal tubular secretion, and the inhibition of (S)(-)-DBCA renal excretion in the presence of the antipode. 4. Probenecid treatment significantly decreased the CLrf,s of both Enantiomers, and the extent of inhibition for the (S)(-)-enantiomer (53%) was significantly higher than that for the antipode (14%). These results show that renal tubular secretion of DBCA involves an anion transport system which prefers the (S)(-)-enantiomer, and that probenecid can preferentially inhibit (S)(-)-enantiomer secretion.
Hideo Yamada - One of the best experts on this subject based on the ideXlab platform.
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Stereoselectivity and enantiomer‐enantiomer interactions in the binding of ibuprofen to human serum albumin
Chirality, 1997Co-Authors: Tomoo Itoh, Yoshikazu Saura, Yasuyuki Tsuda, Hideo YamadaAbstract:Binding of ibuprofen (IB) Enantiomers to human serum albumin (HSA) was studied using a chiral fluorescent derivatizing reagent, which enabled the measurement of IB Enantiomers at a concentration as low as 5 × 10−8 M. Scatchard analyses revealed that there were two classes of binding sites for both Enantiomers. For the high affinity site, the number of the binding sites was one for both Enantiomers, and the binding constant of R-IB was 2.3-fold greater than that of S-IB. The difference in the affinity at the high affinity site may result in the stereoselective binding of IB Enantiomers at therapeutic concentrations. It was confirmed that the high affinity site of IB Enantiomers is Site II (diazepam binding site) by using site marker ligands. Also, significant enantiomer-enantiomer interactions were observed in the binding. The binding data were quantitatively analyzed and a binding model with an assumption of competitive interactions only at the high affinity site simulated the binding characteristics of IB Enantiomers fairly well. Chirality 9:643–649, 1997. © 1997 Wiley-Liss, Inc.
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Stereoselective pharmacokinetics of ibuprofen in rats: effect of enantiomer‐enantiomer interaction in plasma protein binding
Chirality, 1997Co-Authors: Tomoo Itoh, Yasuyuki Tsuda, Jun Maruyama, Hideo YamadaAbstract:Stereoselective pharmacokinetics of ibuprofen (IB) Enantiomers were studied in rats. Unidirectional conversion from R-ibuprofen (R-IB) to S-ibuprofen (S-IB) was observed following intravenous administration. S-IB concentrations in plasma following racemate administration were simulated according to a conventional compartmental model using the parameters obtained after the administration of individual Enantiomers, and resulted in overestimation of S-IB concentrations. Binding of IB Enantiomers measured in rat plasma was stereoselective, the binding of R-IB being more favorable than that of S-IB. Moreover, there are interactions between IB Enantiomers in binding, which may cause the increase of distribution volumes of IB Enantiomers in the presence of their antipodes. Hence simulated S-IB concentrations according to a conventional compartment model were significantly greater than those observed. Indeed, when the enantiomer-enantiomer interactions were taken into account, simulation of S-IB concentrations in plasma following racemate administration was in good agreement with observed values. Therefore, interactions between stereoisomers as well as dispositional stereoselectivity have to be considered when pharmacokinetics of stereoisomers after administration of the racemate are compared to those after administration of individual isomers. Chirality 9:354-361, 1997. © 1997 Wiley-Liss, Inc.
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Stereoselectivity and enantiomer-enantiomer interactions in the binding of ibuprofen to human serum albumin.
Chirality, 1997Co-Authors: Tomoo Itoh, Yoshikazu Saura, Yasuyuki Tsuda, Hideo YamadaAbstract:Binding of ibuprofen (IB) Enantiomers to human serum albumin (HSA) was studied using a chiral fluorescent derivatizing reagent, which enabled the measurement of IB Enantiomers at a concentration as low as 5 × 10−8 M. Scatchard analyses revealed that there were two classes of binding sites for both Enantiomers. For the high affinity site, the number of the binding sites was one for both Enantiomers, and the binding constant of R-IB was 2.3-fold greater than that of S-IB. The difference in the affinity at the high affinity site may result in the stereoselective binding of IB Enantiomers at therapeutic concentrations. It was confirmed that the high affinity site of IB Enantiomers is Site II (diazepam binding site) by using site marker ligands. Also, significant enantiomer-enantiomer interactions were observed in the binding. The binding data were quantitatively analyzed and a binding model with an assumption of competitive interactions only at the high affinity site simulated the binding characteristics of IB Enantiomers fairly well. Chirality 9:643–649, 1997. © 1997 Wiley-Liss, Inc.
Robert B. Raffa - One of the best experts on this subject based on the ideXlab platform.
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complementary and synergistic antinociceptive interaction between the Enantiomers of tramadol
Journal of Pharmacology and Experimental Therapeutics, 1993Co-Authors: Robert B. Raffa, Elmar Friderichs, Wolfgang Reimann, Richard P. Shank, Ellen E. Codd, J. L. Vaught, Henry I. Jacoby, Norma SelveAbstract:The explanation for the co-existence of opioid and nonopioid components of tramadol-induced antinociception appears to be related to the different, but complementary and interactive, pharmacologies of its Enantiomers. The (+) enantiomer had Ki values of only 1.33, 62.4 and 54.0 microM at mu, delta and kappa receptors, respectively. The (-) enantiomer had even lower affinity at the mu and delta sites (Ki = 24.8, 213 and 53.5 microM, respectively. The (+) enantiomer was the most potent inhibitor of serotonin uptake (Ki = 0.53 microM) and the (-) enantiomer was the most potent inhibitor of norepinephrine uptake (Ki = 0.43 microM). Basal serotonin release was preferentially enhanced by the (+) enantiomer and stimulation-evoked norepinephrine release was preferentially enhanced by the (-) enantiomer. The (+) and (-) Enantiomers each independently produced centrally mediated antinociception in the acetylcholine-induced abdominal constriction test (ED50 = 14.1 and 35.0 micrograms i.t., respectively). Racemic tramadol was significantly more potent (P
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Complementary and synergistic antinociceptive interaction between the Enantiomers of tramadol.
The Journal of pharmacology and experimental therapeutics, 1993Co-Authors: Robert B. Raffa, Elmar Friderichs, Wolfgang Reimann, Richard P. Shank, Ellen E. Codd, J. L. Vaught, Henry I. Jacoby, Norma SelveAbstract:The explanation for the co-existence of opioid and nonopioid components of tramadol-induced antinociception appears to be related to the different, but complementary and interactive, pharmacologies of its Enantiomers. The (+) enantiomer had Ki values of only 1.33, 62.4 and 54.0 microM at mu, delta and kappa receptors, respectively. The (-) enantiomer had even lower affinity at the mu and delta sites (Ki = 24.8, 213 and 53.5 microM, respectively. The (+) enantiomer was the most potent inhibitor of serotonin uptake (Ki = 0.53 microM) and the (-) enantiomer was the most potent inhibitor of norepinephrine uptake (Ki = 0.43 microM). Basal serotonin release was preferentially enhanced by the (+) enantiomer and stimulation-evoked norepinephrine release was preferentially enhanced by the (-) enantiomer. The (+) and (-) Enantiomers each independently produced centrally mediated antinociception in the acetylcholine-induced abdominal constriction test (ED50 = 14.1 and 35.0 micrograms i.t., respectively). Racemic tramadol was significantly more potent (P < .05) than the theoretical additive effect of the Enantiomers (antinociceptive synergy). Synergy was also demonstrated (P < .1) in the mouse 55 degrees C hot-plate test (i.p. route) and (P < .05) the rat Randall-Selitto yeast-induced inflammatory nociception model (i.v. and i.p. routes). Critically, the Enantiomers interacted less than synergistically in two side-effects of inhibition of colonic propulsive motility and impairment of rotarod performance. The racemate and the (+) enantiomer were active in a chronic (arthritic) inflammatory pain model. Taken together, these findings provide a rational explanation for the coexistence of dual components to tramadol-induced antinociception and might form the basis for understanding its clinical profile.
M. Nakano - One of the best experts on this subject based on the ideXlab platform.
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Enantiomer-enantiomer interaction of a uricosuric antihypertensive diuretic (DBCA) in renal tubular secretion and stereoselective inhibition by probenecid in the cynomolgus monkey
Xenobiotica, 1993Co-Authors: M. Nakano, Kenji Higaki, S KawaharaAbstract:1. Enantiomer-enantiomer interaction of 5-dimethylsulphamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (DBCA), a uricosuric, diuretic and antihypertensive agent, was studied from the pharmacokinetics of the Enantiomers following intravenous injection of individual Enantiomers and racemate into male cynomolgus monkeys. Also studied was the involvement of the anion transport system in the renal excretion of DBCA by comparison of the pharmacokinetics in probenecid-treated and non-treated animals.2. Separate administration of individual Enantiomers showed higher plasma concentrations of (S)(—)-DBCA than those of the antipode, at an early period after dosing. Both Enantiomers disappeared rapidly from plasma with an elimination half-life (t1/2β) of 0.35–0.38 h. Unbound fractions were 18.9% for the (R)(+)-enantiomer and 10.2% for the (S)(—)-enantiomer. The major portion of both Enantiomers was excreted by 6 h after dosing and 77-78% of the dose was recovered within 48 h, principally as the unchanged d...
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Enantiomer-enantiomer interaction of a uricosuric antihypertensive diuretic (DBCA) in renal tubular secretion and stereoselective inhibition by probenecid in the cynomolgus monkey
Xenobiotica; the fate of foreign compounds in biological systems, 1993Co-Authors: M. Nakano, Kenji Higaki, S KawaharaAbstract:1. Enantiomer-enantiomer interaction of 5-dimethylsulphamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxyl ic acid (DBCA), a uricosuric, diuretic and antihypertensive agent, was studied from the pharmacokinetics of the Enantiomers following intravenous injection of individual Enantiomers and racemate into male cynomolgus monkeys. Also studied was the involvement of the anion transport system in the renal excretion of DBCA by comparison of the pharmacokinetics in probenecid-treated and non-treated animals. 2. Separate administration of individual Enantiomers showed higher plasma concentrations of (S)(-)-DBCA than those of the antipode, at an early period after dosing. Both Enantiomers disappeared rapidly from plasma with an elimination half-life (t1/2 beta) of 0.35-0.38 h. Unbound fractions were 18.9% for the (R)(+)-enantiomer and 10.2% for the (S)(-)-enantiomer. The major portion of both Enantiomers was excreted by 6 h after dosing and 77-78% of the dose was recovered within 48 h, principally as the unchanged drug. Tubular secretion contributed significantly to the renal excretion of DBCA, because tubular secretion clearance values of unbound drug (CLrf,s) were 14- to 29-fold greater than creatinine clearance. 3. The presence of the antipode decreased the tubular secretion clearance (CLrf,s) value of unbound (S)(-)-enantiomer by 30%, and tended to decrease that for the unbound (R)(+)-enantiomer, although not significantly. This indicates the occurrence of enantiomer-enantiomer interaction in the process of renal tubular secretion, and the inhibition of (S)(-)-DBCA renal excretion in the presence of the antipode. 4. Probenecid treatment significantly decreased the CLrf,s of both Enantiomers, and the extent of inhibition for the (S)(-)-enantiomer (53%) was significantly higher than that for the antipode (14%). These results show that renal tubular secretion of DBCA involves an anion transport system which prefers the (S)(-)-enantiomer, and that probenecid can preferentially inhibit (S)(-)-enantiomer secretion.
