The Experts below are selected from a list of 135 Experts worldwide ranked by ideXlab platform
Katsuji Yamashita - One of the best experts on this subject based on the ideXlab platform.
-
in vitro metabolism of a Rifamycin Derivative by animal and human liver microsomes whole blood and expressed human cyp3a isoform
Xenobiotica, 1996Co-Authors: Tatsumasa Mae, Kazunori Hosoe, Kenji Fujii, Katsuji Yamashita, Takehiko Yamane, Takayoshi Hidaka, Takehisa OhashiAbstract:1. In vitro metabolism of a Rifamycin Derivative, benzoxazinoRifamycin KRM-1648, was studied using mouse, rat, guinea pig, dog, monkey and human liver microsomes. 30-Hydroxy-KRM-1648 (M2) was produced in mouse, dog, monkey and human microsomes. 25-Deacetyl-KRM-1648 (M1) was produced in dog and human microsomes, but not in mouse or monkey microsomes. Neither M1 nor M2 was detected in rat or guinea pig microsomes. 2. In dog and human liver microsomes the formation of M2 was dependent on NADPH, but the formation of M1 was not. 3. In vitro metabolism of the parent compound was studied in whole blood in some species. Only M1 was detected in mouse and rat blood, and not in dog and human blood. 4. These findings demonstrated that the metabolite pattern in dog resembled that in man, and suggested that the 30-hydroxylation of KRM-1648 was mediated by cytochrome P450, but that the 25-deacetylation was not. 5. Among the ten recombinant human P450 isoforms used, only the cell lysates including CYP3A3 and CYP3A4 catalysed the M2 formation from KRM-1648.
-
identification and antimicrobial activity of urinary metabolites of a Rifamycin Derivative in dog
Xenobiotica, 1996Co-Authors: Kazunori Hosoe, Tatsumasa Mae, Kenji Fujii, Katsuji Yamashita, Takehiko Yamane, Takayoshi Hidaka, Takehisa OhashiAbstract:1. Three metabolites of the antimicrobial agent 3'-hydroxy-5'-(4-isobutyl-1-piper-azinyl)benzoxazinoRifamycin (KRM-1648) were isolated from dog urine obtained after administration of a single oral dose. These metabolites of KRM-1648 were identified by mass spectrometry and 1H and 13C-nmr spectrometry.2. Three metabolites of KRM-1648 were identified as 25-deacetyl KRM-1648, 30-hydroxy KRM-1648 and 25-deacetyl-30-hydroxy KRM-1648.3. The antimicrobial activities of 25-deacetyl KRM-1648 were comparable with those of the parent compound, whereas 30-hydroxy KRM-1648 was equipotent and 2–8-fold less active than the parent compound against bacteria and mycobacteria, respectively.
-
bactericidal action at low doses of a new Rifamycin Derivative 3 hydroxy 5 4 isobutyl 1 piperazinyl benzoxazinoRifamycin krm 1648 on mycobacterium leprae inoculated into footpads of nude mice
Leprosy Review, 1992Co-Authors: M Gidoh, K Hosoe, Katsuji Yamashita, Takehiko Yamane, S Tsutsumi, T. HidakaAbstract:Among a series of newly-synthesized benzoxazinoRifamycins, 2 of the 3'-hydroxy-5'-(4-alkyl-1-piperazinyl) Derivatives, named KRM-1648 and KRM-2312, whose respective alkyl residues are isobutyl and isopropyl, were examined for efficacy against nude mouse-model leprosy. KRM-1648 completely inhibited the growth of leprosy bacilli inoculated into nude mouse footpads, even 6 months after the medication had been stopped, when given orally at a daily dose of 0.6 mg/kg, 5 or 6 times weekly, during 3-5 months postinoculation. In comparison, the growth inhibition by KRM-2312 was incomplete under the same conditions, though it was still stronger than that by rifampicin. Complete growth inhibition by KRM-1648 was also observed when it was given orally at a dose of 1 or 3 mg/kg twice weekly during the same period. In contrast, the growth inhibition by rifampicin was only slight at 1 mg/kg and partial at 3 mg/kg under the same condition.
Takehiko Yamane - One of the best experts on this subject based on the ideXlab platform.
-
in vitro metabolism of a Rifamycin Derivative by animal and human liver microsomes whole blood and expressed human cyp3a isoform
Xenobiotica, 1996Co-Authors: Tatsumasa Mae, Kazunori Hosoe, Kenji Fujii, Katsuji Yamashita, Takehiko Yamane, Takayoshi Hidaka, Takehisa OhashiAbstract:1. In vitro metabolism of a Rifamycin Derivative, benzoxazinoRifamycin KRM-1648, was studied using mouse, rat, guinea pig, dog, monkey and human liver microsomes. 30-Hydroxy-KRM-1648 (M2) was produced in mouse, dog, monkey and human microsomes. 25-Deacetyl-KRM-1648 (M1) was produced in dog and human microsomes, but not in mouse or monkey microsomes. Neither M1 nor M2 was detected in rat or guinea pig microsomes. 2. In dog and human liver microsomes the formation of M2 was dependent on NADPH, but the formation of M1 was not. 3. In vitro metabolism of the parent compound was studied in whole blood in some species. Only M1 was detected in mouse and rat blood, and not in dog and human blood. 4. These findings demonstrated that the metabolite pattern in dog resembled that in man, and suggested that the 30-hydroxylation of KRM-1648 was mediated by cytochrome P450, but that the 25-deacetylation was not. 5. Among the ten recombinant human P450 isoforms used, only the cell lysates including CYP3A3 and CYP3A4 catalysed the M2 formation from KRM-1648.
-
identification and antimicrobial activity of urinary metabolites of a Rifamycin Derivative in dog
Xenobiotica, 1996Co-Authors: Kazunori Hosoe, Tatsumasa Mae, Kenji Fujii, Katsuji Yamashita, Takehiko Yamane, Takayoshi Hidaka, Takehisa OhashiAbstract:1. Three metabolites of the antimicrobial agent 3'-hydroxy-5'-(4-isobutyl-1-piper-azinyl)benzoxazinoRifamycin (KRM-1648) were isolated from dog urine obtained after administration of a single oral dose. These metabolites of KRM-1648 were identified by mass spectrometry and 1H and 13C-nmr spectrometry.2. Three metabolites of KRM-1648 were identified as 25-deacetyl KRM-1648, 30-hydroxy KRM-1648 and 25-deacetyl-30-hydroxy KRM-1648.3. The antimicrobial activities of 25-deacetyl KRM-1648 were comparable with those of the parent compound, whereas 30-hydroxy KRM-1648 was equipotent and 2–8-fold less active than the parent compound against bacteria and mycobacteria, respectively.
-
bactericidal action at low doses of a new Rifamycin Derivative 3 hydroxy 5 4 isobutyl 1 piperazinyl benzoxazinoRifamycin krm 1648 on mycobacterium leprae inoculated into footpads of nude mice
Leprosy Review, 1992Co-Authors: M Gidoh, K Hosoe, Katsuji Yamashita, Takehiko Yamane, S Tsutsumi, T. HidakaAbstract:Among a series of newly-synthesized benzoxazinoRifamycins, 2 of the 3'-hydroxy-5'-(4-alkyl-1-piperazinyl) Derivatives, named KRM-1648 and KRM-2312, whose respective alkyl residues are isobutyl and isopropyl, were examined for efficacy against nude mouse-model leprosy. KRM-1648 completely inhibited the growth of leprosy bacilli inoculated into nude mouse footpads, even 6 months after the medication had been stopped, when given orally at a daily dose of 0.6 mg/kg, 5 or 6 times weekly, during 3-5 months postinoculation. In comparison, the growth inhibition by KRM-2312 was incomplete under the same conditions, though it was still stronger than that by rifampicin. Complete growth inhibition by KRM-1648 was also observed when it was given orally at a dose of 1 or 3 mg/kg twice weekly during the same period. In contrast, the growth inhibition by rifampicin was only slight at 1 mg/kg and partial at 3 mg/kg under the same condition.
T. Hidaka - One of the best experts on this subject based on the ideXlab platform.
-
Effect of a new Rifamycin Derivative, rifalazil, on liver microsomal enzyme induction in rat and dog
Xenobiotica, 1998Co-Authors: T. Mae, K Hosoe, T. Yamamoto, T. Hidaka, T. Ohashi, J. M. Kleeman, P. E. AdamsAbstract:1. The effect of a new Rifamycin Derivative, rifalazil (KRM-1648), on liver microsomal enzyme induction was studied in rat and dog with repeated oral administration of the compound. Relative liver weight, cytochrome b5 and P450 contents, enzyme activities of NADPH-cytochrome c reductase, aniline hydroxylase, ρ-nitroanisole O-demethylase, aminopyrine N-demethylase, and erythromycin N-demethylase were measured. 2. In rat, rifalazil treatment at 300 mg/kg/day for 10 days increased cytochrome b5 content but it did not affect liver weight, P450 content or enzyme activities. In contrast, rifampicin and rifabutin increased relative liver weights, cytochrome contents and enzyme activities under similar conditions. 3. In dog, rifalazil did not affect any parameters at 30 or 300 mg/kg/day for 13 weeks. 4. These findings indicate that rifalazil is not an enzyme inducer in rat and dog. This property differs from other Rifamycin Derivatives such as rifampicin and rifabutin.
-
inhibition of the multiplication of mycobacterium leprae in nude mice by intermittent administration of a new Rifamycin Derivative 3 hydroxy 5 4 isobutyl 1 piperazinyl benzoxazinoRifamycin krm 1648 combined with sparfloxacin
Leprosy Review, 1995Co-Authors: M Gidoh, T. Hidaka, S Tsutsumi, G Matsuki, S NakamuraAbstract:Inhibition of the multiplication of Mycobacterium leprae in the footpads of nude mice by the oral administration of sparfloxacin, a new quinolone, and 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl)benzoxazinoRifamycin (KRM-1648), selected from a series of newly synthesized benzoxazinoRifamycins, was studied. When the 2 drugs were administered alternately at intervals of 3 or 4 days, (i.e., each drug was administered once weekly), or simultaneously once weekly, between 3 and 5 months after inoculation of nude mice with M. leprae, 10 mg sparfloxacin and 0.6 mg KRM-1648 per kg bodyweight were sufficient to prevent multiplication of the organisms. Only partial inhibition of multiplication was achieved by alternate administration of 5 mg sparfloxacin and 0.3 mg KRM-1648 per kg, as was the case for 20 mg sparfloxacin per kg or 1 mg KRM-1648, each drug administered alone once weekly. The addition to these 2 drugs of dapsone, administered in the diet in a concentration of 0.001 g per 100 g, enhanced their effect. The potential usefulness of multidrug regimens including these compounds is considered.
-
bactericidal action at low doses of a new Rifamycin Derivative 3 hydroxy 5 4 isobutyl 1 piperazinyl benzoxazinoRifamycin krm 1648 on mycobacterium leprae inoculated into footpads of nude mice
Leprosy Review, 1992Co-Authors: M Gidoh, K Hosoe, Katsuji Yamashita, Takehiko Yamane, S Tsutsumi, T. HidakaAbstract:Among a series of newly-synthesized benzoxazinoRifamycins, 2 of the 3'-hydroxy-5'-(4-alkyl-1-piperazinyl) Derivatives, named KRM-1648 and KRM-2312, whose respective alkyl residues are isobutyl and isopropyl, were examined for efficacy against nude mouse-model leprosy. KRM-1648 completely inhibited the growth of leprosy bacilli inoculated into nude mouse footpads, even 6 months after the medication had been stopped, when given orally at a daily dose of 0.6 mg/kg, 5 or 6 times weekly, during 3-5 months postinoculation. In comparison, the growth inhibition by KRM-2312 was incomplete under the same conditions, though it was still stronger than that by rifampicin. Complete growth inhibition by KRM-1648 was also observed when it was given orally at a dose of 1 or 3 mg/kg twice weekly during the same period. In contrast, the growth inhibition by rifampicin was only slight at 1 mg/kg and partial at 3 mg/kg under the same condition.
Kazunori Hosoe - One of the best experts on this subject based on the ideXlab platform.
-
in vitro metabolism of a Rifamycin Derivative by animal and human liver microsomes whole blood and expressed human cyp3a isoform
Xenobiotica, 1996Co-Authors: Tatsumasa Mae, Kazunori Hosoe, Kenji Fujii, Katsuji Yamashita, Takehiko Yamane, Takayoshi Hidaka, Takehisa OhashiAbstract:1. In vitro metabolism of a Rifamycin Derivative, benzoxazinoRifamycin KRM-1648, was studied using mouse, rat, guinea pig, dog, monkey and human liver microsomes. 30-Hydroxy-KRM-1648 (M2) was produced in mouse, dog, monkey and human microsomes. 25-Deacetyl-KRM-1648 (M1) was produced in dog and human microsomes, but not in mouse or monkey microsomes. Neither M1 nor M2 was detected in rat or guinea pig microsomes. 2. In dog and human liver microsomes the formation of M2 was dependent on NADPH, but the formation of M1 was not. 3. In vitro metabolism of the parent compound was studied in whole blood in some species. Only M1 was detected in mouse and rat blood, and not in dog and human blood. 4. These findings demonstrated that the metabolite pattern in dog resembled that in man, and suggested that the 30-hydroxylation of KRM-1648 was mediated by cytochrome P450, but that the 25-deacetylation was not. 5. Among the ten recombinant human P450 isoforms used, only the cell lysates including CYP3A3 and CYP3A4 catalysed the M2 formation from KRM-1648.
-
identification and antimicrobial activity of urinary metabolites of a Rifamycin Derivative in dog
Xenobiotica, 1996Co-Authors: Kazunori Hosoe, Tatsumasa Mae, Kenji Fujii, Katsuji Yamashita, Takehiko Yamane, Takayoshi Hidaka, Takehisa OhashiAbstract:1. Three metabolites of the antimicrobial agent 3'-hydroxy-5'-(4-isobutyl-1-piper-azinyl)benzoxazinoRifamycin (KRM-1648) were isolated from dog urine obtained after administration of a single oral dose. These metabolites of KRM-1648 were identified by mass spectrometry and 1H and 13C-nmr spectrometry.2. Three metabolites of KRM-1648 were identified as 25-deacetyl KRM-1648, 30-hydroxy KRM-1648 and 25-deacetyl-30-hydroxy KRM-1648.3. The antimicrobial activities of 25-deacetyl KRM-1648 were comparable with those of the parent compound, whereas 30-hydroxy KRM-1648 was equipotent and 2–8-fold less active than the parent compound against bacteria and mycobacteria, respectively.
-
Mechanism of Action of Antimycobacterial Activity of the New BenzoxazinoRifamycin KRM-1648
1995Co-Authors: Tatsumasa Mae, Kazunori HosoeAbstract:mechanism of antimicrobial activity of KRM-1648 (KRM), a new Rifamycin Derivative with potent antimycobacterial activity, was studied. Both KRM and rifampin (RMP) inhibited RNA polymerases from Escherichia coli and Mycobacterium avium at low concentrations: the 50 % inhibitory concentrations (IC50s) of KRM and RMP for E. coli RNA polymerase were 0.13 and 0.10 mg/ml, respectively, while the IC50s forM. avium RNA polymerase were 0.20 and 0.07 mg/ml. Both KRM and RMP exerted weak inhibitory activity against Mycobacterium fortuitum RNA polymerase, rabbit thymus RNA polymerases, E. coli DNA polymerase I, and two types of reverse transcriptases. Uptake of 14C-KRM by M. avium reached 18,000 dpm/mg (dry weight) 1.5 h after incubation, while uptake by E. coli cells was slight. KRM was much more effective in inhibiting uptake of 14C-uracil than was RMP (IC50 of KRM, 0.04 mg/ml; IC50 of RMP, 0.12 mg/ml). These findings suggest, first, that the potent antimycobacterial activity of KRM is due to inhibition of bacterial RNA polymerase and, second, that the activity of KRM against target organisms depends on target cell wall permeability. 39-Hydroxy-59-(4-isobutyl-1-piperazinyl)benzoxazinorifamy-cin (KRM-1648 [KRM]), a newly synthesized Rifamycin deriv-ative, exerts much more potent in vitro and in vivo activities against slowly growing mycobacteria, including those of the Mycobacterium avium complex andMycobacterium tuberculosis
Takehisa Ohashi - One of the best experts on this subject based on the ideXlab platform.
-
in vitro metabolism of a Rifamycin Derivative by animal and human liver microsomes whole blood and expressed human cyp3a isoform
Xenobiotica, 1996Co-Authors: Tatsumasa Mae, Kazunori Hosoe, Kenji Fujii, Katsuji Yamashita, Takehiko Yamane, Takayoshi Hidaka, Takehisa OhashiAbstract:1. In vitro metabolism of a Rifamycin Derivative, benzoxazinoRifamycin KRM-1648, was studied using mouse, rat, guinea pig, dog, monkey and human liver microsomes. 30-Hydroxy-KRM-1648 (M2) was produced in mouse, dog, monkey and human microsomes. 25-Deacetyl-KRM-1648 (M1) was produced in dog and human microsomes, but not in mouse or monkey microsomes. Neither M1 nor M2 was detected in rat or guinea pig microsomes. 2. In dog and human liver microsomes the formation of M2 was dependent on NADPH, but the formation of M1 was not. 3. In vitro metabolism of the parent compound was studied in whole blood in some species. Only M1 was detected in mouse and rat blood, and not in dog and human blood. 4. These findings demonstrated that the metabolite pattern in dog resembled that in man, and suggested that the 30-hydroxylation of KRM-1648 was mediated by cytochrome P450, but that the 25-deacetylation was not. 5. Among the ten recombinant human P450 isoforms used, only the cell lysates including CYP3A3 and CYP3A4 catalysed the M2 formation from KRM-1648.
-
identification and antimicrobial activity of urinary metabolites of a Rifamycin Derivative in dog
Xenobiotica, 1996Co-Authors: Kazunori Hosoe, Tatsumasa Mae, Kenji Fujii, Katsuji Yamashita, Takehiko Yamane, Takayoshi Hidaka, Takehisa OhashiAbstract:1. Three metabolites of the antimicrobial agent 3'-hydroxy-5'-(4-isobutyl-1-piper-azinyl)benzoxazinoRifamycin (KRM-1648) were isolated from dog urine obtained after administration of a single oral dose. These metabolites of KRM-1648 were identified by mass spectrometry and 1H and 13C-nmr spectrometry.2. Three metabolites of KRM-1648 were identified as 25-deacetyl KRM-1648, 30-hydroxy KRM-1648 and 25-deacetyl-30-hydroxy KRM-1648.3. The antimicrobial activities of 25-deacetyl KRM-1648 were comparable with those of the parent compound, whereas 30-hydroxy KRM-1648 was equipotent and 2–8-fold less active than the parent compound against bacteria and mycobacteria, respectively.
