METABOLIC N-HYDROXYLATION OF PENTAMIDINE INVITRO

被引:47
作者
BERGER, BJ
LOMBARDY, RJ
MARBURY, GD
BELL, CA
DYKSTRA, CC
HALL, JE
TIDWELL, RR
机构
[1] UNIV N CAROLINA,SCH MED,DEPT PATHOL,CHAPEL HILL,NC 27599
[2] UNIV N CAROLINA,SCH PUBL HLTH,DEPT PARASITOL & LAB PRACTICE,CHAPEL HILL,NC 27599
[3] UNIV N CAROLINA,SCH PUBL HLTH,DEPT ENVIRONM SCI & ENGN,CHAPEL HILL,NC 27599
[4] UNIV N CAROLINA,SCH PHARM,DEPT MED CHEM,CHAPEL HILL,NC 27599
关键词
D O I
10.1128/AAC.34.9.1678
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
By using high-performance liquid chromatography, the in vitro conversion of pentamidine to the corresponding amidoximes (N-hydroxypentamidine and N,N'-dihydroxypentamidine) was studied in supernatants of rat liver homogenate centrifuged at 9,000 x g. The presence of the two amidoxime peaks in chromatograms was confirmed by liquid secondary ion mass spectrometry and by unequivocal synthesis of the suspected metabolites. The metabolic reactions were found to be catalyzed by the cytochrome P-450 system (mixed-function oxidases). The formation of the monohydroxylated product was found to have a K(m) of 0.48 mM and a V(max) of 29.50 pmol/min per mg of protein, while the dihydroxylated metabolite had a K(m) of 0.73 mM and a V(max) of 4.10 pmol/min per mg of protein. N,N'-Dihydroxypentamidine was found to have highly reduced antiprotozoal activity in vitro relative to that of pentamidine, and neither of the hydroxylated metabolites nor pentamidine was found to be significantly mutagenic by the Ames test. Contrary to previous reports, pentamidine is readily metabolized to at least two hydroxylated products, and this conversion may be relevant to the clinical use of the compound and to future drug design.
引用
收藏
页码:1678 / 1684
页数:7
相关论文
共 38 条
  • [1] HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHIC METHOD FOR THE QUANTIFICATION OF SEVERAL DIAMIDINE COMPOUNDS WITH POTENTIAL CHEMOTHERAPEUTIC VALUE
    BERGER, BJ
    HALL, JE
    TIDWELL, RR
    [J]. JOURNAL OF CHROMATOGRAPHY-BIOMEDICAL APPLICATIONS, 1989, 494 : 191 - 200
  • [2] THE DISTRIBUTION OF MULTIPLE DOSES OF PENTAMIDINE IN RATS
    BERGER, BJ
    HALL, JE
    TIDWELL, RR
    [J]. PHARMACOLOGY & TOXICOLOGY, 1990, 66 (03): : 234 - 236
  • [3] USE OF A NEW BIOASSAY TO STUDY PENTAMIDINE PHARMACOKINETICS
    BERNARD, EM
    DONNELLY, HJ
    MAHER, MP
    ARMSTRONG, D
    [J]. JOURNAL OF INFECTIOUS DISEASES, 1985, 152 (04) : 750 - 754
  • [4] THE SENSITIVITY OF GIARDIA-INTESTINALIS TO DRUGS INVITRO
    BOREHAM, PFL
    PHILLIPS, RE
    SHEPHERD, RW
    [J]. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 1984, 14 (05) : 449 - 461
  • [5] CHARACTERISTICS OF THE MICROSOMAL N-HYDROXYLATION OF BENZAMIDINE TO BENZAMIDOXIME
    CLEMENT, B
    ZIMMERMANN, M
    [J]. XENOBIOTICA, 1987, 17 (06) : 659 - 667
  • [6] ENZYMATIC REDUCTION OF BENZAMIDOXIME TO BENZAMIDINE
    CLEMENT, B
    SCHMITT, S
    ZIMMERMANN, M
    [J]. ARCHIV DER PHARMAZIE, 1988, 321 (12) : 955 - 956
  • [7] THE N-OXIDATION OF BENZAMIDINES INVITRO
    CLEMENT, B
    [J]. XENOBIOTICA, 1983, 13 (08) : 467 - 473
  • [8] HEPATIC-MICROSOMAL N-DEMETHYLATION OF N-METHYLBENZAMIDINE - N-DEALKYLATION VS N-OXYGENATION OF AMIDINES
    CLEMENT, B
    ZIMMERMANN, M
    [J]. BIOCHEMICAL PHARMACOLOGY, 1987, 36 (19) : 3127 - 3133
  • [9] MECHANISM OF THE MICROSOMAL N-HYDROXYLATION OF PARA-SUBSTITUTED BENZAMIDINES
    CLEMENT, B
    ZIMMERMANN, M
    [J]. BIOCHEMICAL PHARMACOLOGY, 1988, 37 (24) : 4747 - 4752
  • [10] CLEMENT B, 1985, ARZNEIMITTEL-FORSCH, V35-2, P1009