METABOLISM AND METABOLITE PHARMACOKINETICS OF BRB-I-28, A CLASS IB ANTIARRHYTHMIC AGENT

被引:12
作者
CHEN, CL
SANGIAH, S
BOURNE, DWA
RODER, JD
CHEN, H
ALAVI, FK
CLARKE, CR
GARRISON, GL
BERLIN, KD
COUCH, KM
ZISMAN, SA
SCHERLAG, BJ
LAZZARA, R
VANDERHELM, D
机构
[1] OKLAHOMA STATE UNIV,COLL VET MED,DEPT PHYSIOL SCI,STILLWATER,OK 74078
[2] OKLAHOMA STATE UNIV,DEPT CHEM,STILLWATER,OK 74078
[3] UNIV OKLAHOMA,VET AFFAIRS MED CTR,HLTH SCI CTR,OKLAHOMA CITY,OK
[4] UNIV OKLAHOMA,DEPT CHEM,NORMAN,OK 73019
关键词
BRB-I-28; ANTIARRHYTHMICS; METABOLISM;
D O I
10.1007/BF03226370
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The metabolism of BRB-I-28 (7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane), a novel class Ib antiarrhythmic agent, was characterized in vivo in dogs and rats and in vitro with rat liver microsomal preparations containing a NADPH-generating system. In dogs, rats and the in vitro hepatic microsomal oxidation system, BRB-I-28 was extensively metabolized to form 7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane-3-oxide (I), a major metabolite. The metabolite I was produced via S-oxidation, presumably by the hepatic P-450 system. Formation of a minor metabolite, 7-benzoyl-3-thia-7-azabicyclo[3.3.1]nonane (II) via the oxidation of the benzylic site was also identified in rats. Following intravenous and oral administration of BRB-I-28 to dogs, the plasma concentration of major metabolite I could be best described by a I-compartmental model. The plasma AUC of metabolite I was 20% (i.v.) and 179.4% (oral) of that of the parent BRB-I-28, respectively, suggesting that BRB-I-28 was metabolized significantly by the first pass effect following oral administration. Extensive metabolism of BRB-I-28 to form metabolites I and II, which have demonstrated much lower antiarrhythmic activities, further supports previously observed pharmacodynamic and pharmacokinetic findings.
引用
收藏
页码:151 / 161
页数:11
相关论文
共 31 条
  • [1] DISPOSITION OF BRB-I-28 (7-BENZYL-7-AZA-3-THIABICYCLO[3.3.1]NONANE HYDROPERCHLORATE), A NOVEL ANTIARRHYTHMIC AGENT
    ALAVI, FK
    CLARKE, CR
    SANGIAH, S
    BERLIN, KD
    ZISMAN, SA
    CHEN, CL
    GARRISON, G
    SCHERLAG, BJ
    LAZZARA, R
    [J]. DRUG INVESTIGATION, 1991, 3 (05): : 317 - 323
  • [2] SYNTHESIS, CONFORMATIONAL-ANALYSIS, AND ANTIARRHYTHMIC PROPERTIES OF 7-BENZYL-3-THIA-7-AZABICYCLO[3.3.1]NONAN-9-ONE, 7-BENZYL-3-THIA-7-AZABICYCLO[3.3.1]NONANE HYDROPERCHLORATE, AND 7-BENZYL-9-PHENYL-3-THIA-7-AZABICYCLO[3.3.1]NONAN-9-OL HYDROPERCHLORATE AND DERIVATIVES - SINGLE-CRYSTAL X-RAY-DIFFRACTION ANALYSIS AND EVIDENCE FOR CHAIR CHAIR AND CHAIR BOAT CONFORMERS IN THE SOLID-STATECL
    BAILEY, BR
    BERLIN, KD
    HOLT, EM
    SCHERLAG, BJ
    LAZZARA, R
    BRACHMANN, J
    VANDERHELM, D
    POWELL, DR
    PANTALEO, NS
    RUENITZ, PC
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1984, 27 (06) : 758 - 767
  • [3] Berlin K. D., 1992, US Patent, Patent No. [5084572, US5084572A1]
  • [4] Berlin K. D., UNPUB
  • [6] CHEN CL, 1994, RES COMMUN MOL PATH, V85, P193
  • [7] BRB-I-28 - A NOVEL CLASS IB ANTIARRHYTHMIC AGENT
    CHEN, CL
    SANGIAH, S
    BERLIN, KD
    SCHERLAG, B
    PATTERSON, E
    LAZZARA, R
    [J]. CARDIOVASCULAR DRUG REVIEWS, 1994, 12 (03): : 237 - 253
  • [8] PHARMACOKINETICS AND PLASMA-PROTEIN BINDING OF BRB-I-28, A NOVEL ANTIARRHYTHMIC AGENT, IN DOGS
    CHEN, CL
    SANGIAH, S
    RODER, JD
    CHEN, H
    BERLIN, KD
    GARRISON, GL
    SCHERLAG, BJ
    LAZZARA, R
    PATTERSON, E
    [J]. DRUG INVESTIGATION, 1993, 6 (04): : 237 - 243
  • [9] CHEN CL, 1992, RES COMMUN CHEM PATH, V78, P3
  • [10] HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHIC DETERMINATION OF BRB-I-28, A NOVEL ANTIARRHYTHMIC AGENT, IN DOG PLASMA AND URINE
    CHEN, CL
    LESSELEY, BA
    CLARKE, CR
    RODER, JD
    SANGIAH, S
    BERLIN, KD
    GARRISON, GL
    SCHERLAG, BJ
    LAZZARA, R
    PATTERSON, E
    [J]. JOURNAL OF CHROMATOGRAPHY-BIOMEDICAL APPLICATIONS, 1992, 583 (02): : 274 - 279