Biopharmaceutical characterization of 450191-S, a ring-opened derivative of 1,4-benzodiazepine. I Active metabolite levels in rat plasma.

Koike, Masahiro; Norikura, Ryo; Yoshimori, Takeo; Futaguchi, Shinya; Sugeno, Koichi

doi:10.1248/bpb1978.9.563

Cited by 7 publications

(5 citation statements)

References 5 publications

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“…Since the Fig. 2A indicate that the metabolic conversion of metabolite M-1 to M-2 was followed by that to M-A, as described previously (14); and the con version of M-2 to M-A was supposed to be a rate-limiting step in the major pathway of 450191-S metabolism when high amounts of 450191-S were administered.…”

Section: Plasma Concentrationsmentioning

confidence: 64%

“…1, metabolite M-1 is converted enzymatically to M-2 via the formation of M-D, and the lower plasma concentration of metabolite M-1 even at the peak level suggests its rapid conversion to M-D p/us M-2 in rats pretreated with pheno barbital or 450191 -S (600 mg/kg). Me tabolites M-2 plus M-D were further con verted to M-3 via the formation of M-A (14), and the lower plasma concentrations of M-2 plus M-D in phenobarbital or 450191 -S pretreated rats (Fig. 4B) suggest the rapid conversion of M-2 to M-A and other ring hydroxylated metabolites.…”

Section: Plasma Concentrationsmentioning

confidence: 95%

“…1. These metabolites are mainly excreted to bile (14), and thus their hepatocellular dis tribution is thought to be the most important factor for understanding the correlation between the hepatic enzyme activity and the levels of 450191-S metabolites. However, the plasma level profiles of the metabolites may reflect the metabolic pattern in liver, and they are also important for obtaining thera peutic correlations.…”

Section: Plasma Concentrationsmentioning

confidence: 99%

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Effect of change of hepatic drug-metabolizing activity on plasma concentrations of major metabolites of the new sleep inducer 450191-S, a 1H-1,2,4-triazolyl benzophenone derivative.

1987

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Abstract-Plasma concentrations of the major metabolites of 450191-S, a new sleep inducer which is a 1 H-1,2,4-triazolyl benzophenone derivative, were deter mined in rats. Under the HPLC conditions employed, several major metabolites were detected in plasma, and thus the plasma concentration-time profiles for these metabolites were checked in rats in various states. When the animals were pre treated with high doses of 450191-S (200 or 600 mg/kg for 5 or 3 days, respectively) to induce hepatic drug-metabolizing enzymes, plasma concentrations of the meta bolites after oral administration of a dose of 200 mg/kg of 450191-S decreased markedly depending on the induced enzyme activity. Pretreatment of rats with phenobarbital also caused decreased plasma levels of metabolites, which were almost the same as those in 450191-S-pretreatment. On the other hand, adminis tration of beta-naphthoflavone to rats led to higher plasma levels of metabolites, and slower elimination compared with those in the control and 450191-5 or phenobarbital-pretreated rats. These results indicate that plasma levels of me tabolites are regulated by the drug-metabolizing enzymes in the liver. It also suggests the participation of some specific forms of cytochrome P-450 in the biotransformation of 450191 -S and its metabolites.

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Section: Plasma Concentrationsmentioning

confidence: 64%

Section: Plasma Concentrationsmentioning

confidence: 95%

Section: Plasma Concentrationsmentioning

confidence: 99%

See 1 more Smart Citation

Effect of change of hepatic drug-metabolizing activity on plasma concentrations of major metabolites of the new sleep inducer 450191-S, a 1H-1,2,4-triazolyl benzophenone derivative.

1987

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“…The metabolism of 450191-S was studied in various animals, [47][48][49] and the metabolic pathway was clariˆed as shown in Fig. 3.…”

Section: Induction Of Hepatic P450 Enzyme Systemmentioning

confidence: 99%

Safety Evaluation and Drug Development based on Biological Fate of Drugs —Efforts Made to Overcome Drug Interaction in Drug Development—

Matsubara¹

2002

Drug Metabolism and Pharmacokinetics

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1. Assay methods to detect drug interaction in toxicological samples were established by determining cytochrome P450 content and its activity in liver samples. The O-dealkylation reaction of 7-alkoxycoumarin was indicated to reflect changes in the molecular forms of P450s, and the enzyme induction or inhibition in the toxicological samples was easily detected by using the established methods. 2. During toxicological studies of 450191-S or the sleep inducer rilmazafone, a phenobarbital type-induction of hepatic drug metabolizing enzymes was observed in animals, and the doses required for the induction differed markedly between rats and dogs. Enzyme induction was caused by some specific metabolites of 450191-S, and the plasma concentrations of these metabolites were comparable when the enzyme induction was developed in both animals. 3. A nonsteroidal antiinflammatory compound 480156-S showed a slight or no effect on microsomal drug metabolizing activity in rats. On the other hand, repeated administration of this compound to humans resulted in a marked decrease in the oxidative metabolism of 480156-S, followed by a marked increase in the plasma concentrations of the compound. When volunteers were given 480156-S followed by several drugs, such as tolubutamide, the plasma clearance was delayed remarkably, indicating a severe drug interaction. 4. Cytochrome P450 belonging to the CYP2C family was indicated to participate in the oxidative metabolism of 480156-S in both rat and human liver microsomes. The preincubation of microsomes with 480156-S caused a concentration-dependent inhibition of CYP2C-dependent tolubutamide hydroxylation reaction in both rats and humans. There was a marked species difference in the susceptibility to the inhibitory effect of 480156-S, and the concentration required to inhibit rat CYP2C was almost 10 times higher than that required in humans. 5. The cephem antibiotics having N-methyltetrazolethiol (NMTT) at the 3'-position substituent were demonstrated to inhibit mitochondrial low K(m) aldehyde dehydrogenase (ALDH), and produced disulfiram-like (Antabuse) reaction during alcohol metabolism. Pharmacokinetic studies indicated that NMTT released from the antibiotics in bile duct or intestine cause the inhibitory action followed by the development of disulfiram-like reaction. 6. Attempts had been made to develop new cephem antibiotics lacking the disulfiram-like reaction by changing the chemical structure of 3'-position substituents, and a hydroxyethyltetrazolethiol was found not to inhibit the enzyme. Based on this result, together with the antibacterial activity, we have developed a new oxacephem antibiotic flomoxef (6315-S). Flomoxef showed no disulfiram-like reaction both in rats and human.

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“…4 The concentration of M1 in the systemic plasma after oral administration of RZ has been reported to be higher than that observed after administration of M1,5 due to the lower hepatic extraction of DG than M1. 6 The factors by which the hepatic intrinsic clearance is determined are the permeability across the sinusoidal membrane and the sequestration (metabolism and/or excretion) ability in the liver.7 However, it remains to be clarified which process is responsible for the difference in first-pass elimination of DG and M1.…”

Section: Introduction Rilmazafone (Rz) Is a Potentially Orally Activementioning

confidence: 99%

Comparative hepatic transport of desglycylated and cyclic metabolites of rilmazafone in rats: Analysis by multiple indicator dilution method

Muranushi

Miyauchi

Suzuki

et al. 1993

Biopharm & Drug Disp

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Rilmazafone (RZ) is an orally active sleep inducer which can be activated to its cyclic form (M1) via the labile desglycylated metabolite (DG). In this scheme, RZ is exclusively metabolized to DG and M1 by aminopeptidases in the small intestine. The concentration of M1 in the systemic plasma after oral administration of RZ has been reported to be higher than that observed after administration of M1, due to the lower hepatic extraction of DG than M1 (Koike et al., Drug Metab. Dispos., 16, 609 (1988)). In the present study, the disposition of DG and M1 in rat liver was investigated, using the multiple indicator dilution method. The hepatic availabilities (F) of DG and M1, assessed from the recovery into the hepatic vein, were 0.16 and 0.07, respectively, which was consistent with the previous in vivo finding that the first-pass elimination of M1 was greater than that of DG. The kinetic analysis based on the distributed model showed that the influx (k'1) and efflux (k'2) rate constants for M1 were larger than those for DG, whereas no significant difference in the sequestration rate constant (k'3) was observed between the two ligands. Based on the concept proposed by Miyauchi et al. (J. Pharmacokinet. Biopharm., 15, 25 (1987)), it was suggested that the determinant factor of the hepatic intrinsic clearance was the influx clearance for both ligands, because the values of k'2 for each ligand were much smaller than the respective k'3 values. It was concluded that the higher plasma concentration of M1 after oral administration of RZ than that observed after administration of M1 is due to the fact that the hepatic uptake of DG is lower than that of M1.

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Biopharmaceutical characterization of 450191-S, a ring-opened derivative of 1,4-benzodiazepine. I Active metabolite levels in rat plasma.

Cited by 7 publications

References 5 publications

Effect of change of hepatic drug-metabolizing activity on plasma concentrations of major metabolites of the new sleep inducer 450191-S, a 1H-1,2,4-triazolyl benzophenone derivative.

Effect of change of hepatic drug-metabolizing activity on plasma concentrations of major metabolites of the new sleep inducer 450191-S, a 1H-1,2,4-triazolyl benzophenone derivative.

Safety Evaluation and Drug Development based on Biological Fate of Drugs —Efforts Made to Overcome Drug Interaction in Drug Development—

Comparative hepatic transport of desglycylated and cyclic metabolites of rilmazafone in rats: Analysis by multiple indicator dilution method

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