METABOLISM OF THEOPHYLLINE AND ITS INHIBITION BY FLUOROQUINOLONES IN RAT HEPATIC MICROSOMES

被引：6

作者：

DAVIS, JD ^{[1
]}

AARONS, L ^{[1
]}

HOUSTON, JB ^{[1
]}

机构：

[1] UNIV MANCHESTER,DEPT PHARM,MANCHESTER M13 9PL,LANCS,ENGLAND

来源：

XENOBIOTICA | 1995年 / 25卷 / 06期

关键词：

D O I：

10.3109/00498259509061875

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

1. The effects of beta-naphthoflavone, dexamethasone, phenobarbitone and isosafrole on the metabolism of theophylline by rat liver microsomes have been studied. Only beta-naphthoflavone, a known P4501A inducer, increased the rate of 1-methylxanthine formation (3-fold), whereas all the inducers studied increased the rate of 1,3-dimethyluric acid production (2.5-3-fold). 2. To study the effects of a range of fluoroquinolones on theophylline metabolism, beta-naphthoflavone-induced microsomes were used, as the ratio for metabolite production rates was similar to that of untreated microsomes (4:1,3-dimethyluric acid:l-methylxanthine at 2 mM theophylline). High concentrations of fluoroquinolones (0.5-1.5 mM) were required to affect microsomal theophylline metabolism. l-Methylxanthine was more sensitive to fluoroquinolone inhibition by enoxacin, ciprofloxacin, norfloxacin and pipemidic acid than 1,3-dimethyluric acid; CP67015, had a significant effect on 1,3-dimethyluric acid production only; binfloxacin had no effect on either pathway. 3. Ethoxycoumarin, a rapidly metabolized substrate, was also investigated as a surrogate for theophylline in in vitro experiments. Fluoroquinolone inhibition of ethoxycoumarin O-de-ethylation in beta-naphthoflavone-induced microsomes was quantitatively greater but qualitatively similar to theophylline metabolism (IC50s 440-870 mu M at 2 mu M 7-ethoxycoumarin). 4. These data are comparable with previous rat experiments irt vivo, indicating that enoxacin, ciprofloxacin and norfloxacin have similar intrinsic activity in the inhibition of theophylline metabolism.

引用

页码：563 / 573

页数：11

共 27 条

[1]

Anadon A., Martinez-Larranaga M.R., Fernandez M.C., Diaz M.J., Bringar P., Effect of ciprofloxacin on antipyrine pharmacokinetics and metabolism in rats, Antimicrobial Agents and Chemotherapy, 34, pp. 2148-2151, (1990)

[2]

Beckmann J., Elsaber W., Gundert-Remy U., Hertrampf R., Enoxacin—a potent inhibitor of theophylline metabolism, European Journal of Clinical Pharmacology, 33, pp. 227-230, (1987)

[3]

Berthou F., Flinois J.-P., Ratanasavanh D., Beaune P., Riche C., Guillouzo A., Evidence for involvement of several cytochromes P-450 in the first steps of caffeine metabolism by human liver microsomes, Drug Metabolism and Disposition, 19, pp. 561-567, (1991)

[4]

Burke M.D., Mayer R.T., Inherent specificities of purified cytochromes P-450 and P-448 toward biphenyl hydroxylation and ethoxyresorufin deethylation, Drug Metabolism and Disposition, 2, pp. 583-587, (1974)

[5]

Campbell M.E., Grant D.M., Inaba T., Kalow W., Biotransformation of caffeine, paraxanthine, theophylline and theobromine by polycyclic aromatic hydrocarbon-inducible cytochrome(s) P-450 in human liver microsomes, Drug Metabolism and Disposition, 15, pp. 237-249, (1987)

[6]

Davis J.D., Aarons L., Houston J.B., Relationship between enoxacin and ciprofloxacin plasma concentrations and theophylline disposition, Pharmaceutical Research, 11, pp. 1424-1428, (1994)

[7]

Davis J.D., Aarons L., Houston J.B., Effect of norfloxacin on theophylline disposition: a comparison with other fluoroquinolones, Pharmaceutical Research, 12, pp. 257-262, (1995)

[8]

Edwards D.J., Bowles S.K., Svensson C.K., Rybak M.M., Inhibition of drug metabolism by quinolone antibiotics, Clinical Pharmacokinetics, 15, pp. 194-204, (1988)

[9]

Fuhr U., Strobl G., Manaut F., Anders E.-M., Sorgel F., Lopez-de-Brinas E., Chu D.T.W., Pernet A.G., Mahr G., Sanz F., Staib A.H., Quinolone antibacterial agents: relationship between structure and in vitro inhibition of the human cytochrome P450 isoform CYP1A2, Molecular Pharmacology, 43, pp. 191-199, (1992)

[10]

Lake B.G., Preparation and characterization of microsomal fractions for studies of xenobiotic metabolism, Biochemical Toxicology—A Practical Approach, (1987)

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