Biotransformation of the methylenedioxy moeity of oxolinic acid in man

DiCarlo, Frederick J.; Crew, Malcolm C.; Greenough, R. Clive

doi:10.1016/0003-9861(68)90255-5

Cited by 20 publications

(4 citation statements)

References 6 publications

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“…Bile and urine were sometimes treated with 1,000 U of ,B-glucuronidase B-10 (Sigma Chemical Co., St. Louis, Mo.) per ml as reported previously (2) threefold, the standard solutions were made in the presence of plasma to the same content as the samples. After incubation at 37°C for 18 h, the diameters of the inhibitory zones were measured and converted to concentrations by using video analyzing equipment (502A; DAC Engineering Co., Ltd., Kyoto, Japan) connected to a personal computer (PC-9801vm; NEC Corp., Tokyo, Japan).…”

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Pharmacokinetics of a novel quinolone, AT-4140, in animals

Nakamura

Kurobe

Ohue

et al. 1990

Antimicrob Agents Chemother

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The pharmacokinetics of 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(cis-3,5-dimethyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (AT-4140) in experimental animals given a single oral dose of 5 mg/kg were studied. The mean peak levels of AT-4140 in plasma of mice, rats, dogs, and monkeys were 0.25, 0.50, 1.14, and 0.49 ,ug/ml, respectively, with mean elimination half-lives of 5.0, 3.8, 8.0, and 11.7 h, respectively. The oral bioavailability of AT-4140 calculated from the ratio of the areas under the concentration-time curve after oral and intravenous administration was 77% in dogs. The levels of AT-4140 in tissue in mice and rats were 1 to 11 times higher than the levels in plasma and 4 to 9 times higher than those of ciprofloxacin in mice. The mean 24-h biliary recovery of AT-4140 in rats was 5.6% of the dose and became 21.3% after (3-glucuronidase treatment. The mean 48-h urinary recoveries of AT-4140 in mice, rats, dogs, and monkeys were 6.7, 12.9,-8.6, and 12.7%, respectively, of the dose and were 7.8, 16.3, 8.9, and 18 Nakamura, Chem. Abstr. 107:236733v, 1987) and ciprofloxacin (4) were synthesized in our laboratory as reported previously. Doses and concentrations of the drugs are expressed in terms of the free bases.Animals. The animals used were male Std-ddY mice weighing 22 to 38 g, male Wistar rats weighing 190 to 270 g, male beagle dogs weighing 11 to 13 kg, and male cynomolgus monkeys weighing 3.7 to 5.4 kg.Drug administration. For oral administration, AT-4140 was suspended in 0.2% carboxymethylcellulose sodium solution (for mice and rats) or 0.5% gum tragacanth solution (for monkeys) and ciprofloxacin was dissolved in deionized water to avoid its aggregation in 0.2% carboxymethylcellulose sodium solution (for mice). Both the drugs were packed in gelatin capsules for oral administration to dogs. For intravenous administration, the drugs were dissolved in physiological saline with an appropriate amount of NaOH if necessary. The drugs were administered once at a dose of 5 mg/kg to animals that had fasted overnight, unless otherwise specified.Preparation of assay samples. Blood was withdrawn by cardiac puncture from mice and rats under ether anesthesia at 0.25, 0.5, 1, 2, 4, 6, and 8 h postadministration and by * Corresponding author.venipuncture from dogs and monkeys at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after oral administration and 0.1, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after intravenous administration. Blood samples were centrifuged to separate the plasma. Organs and tissues were harvested from exsanguinated mice 0.5, 1, 2, 4, 6, and 8 h postadministration and from exsanguinated rats 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h postadministration. Spinal fluid was taken from the same rats by puncturing the atlanto-occipital membrane by the method of Yaksh and Rudy (17) before exsanguination. Tissue extracts were prepared as described previously (9). Bile was collected from rats through a polyethylene catheter introduced into the common bile duct by surgery and pooled for 0 to 3, 3 to 6, and 6 to 24...

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Pharmacokinetics of a novel quinolone, AT-4140, in animals

Nakamura

Kurobe

Ohue

et al. 1990

Antimicrob Agents Chemother

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“…In insects and mammals, the metabolism of 1,2‐(methylenedioxy)benzene compounds in the presence of NADPH 2 yields catechols with the release of formate[15]. One of the hydroxyl groups of the catechol may subsequently be methylated[16], as in the methoxylated and glucuronide‐conjugated human cinoxacin metabolite detected in urine[5]. However, B. bassiana cleaved the dioxolo ring without methylating either of the resulting hydroxyl groups.…”

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confidence: 99%

Transformation of cinoxacin byBeauveria bassiana

Parshikov

Moody

Heinze

et al. 2002

FEMS Microbiology Letters

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The ability of the fungus Beauveria bassiana ATCC 7159 to transform the antibacterial agent cinoxacin was investigated. Cultures in sucrose-peptone broth were dosed with cinoxacin, grown for 20 days, and then extracted with ethyl acetate. Two metabolites were detected and purified by high-performance liquid chromatography. The major metabolite was identified by mass and proton nuclear magnetic resonance spectra as 1-ethyl-1,4-dihydro-3-(hydroxymethyl)[1,3]dioxolo[4,5-g]cinnolin-4-one and the minor metabolite was identified as 1-ethyl-1,4-dihydro-6,7-dihydroxy-3-(hydroxymethyl)cinnolin-4-one. B. bassiana also reduced quinoline-3-carboxylic acid to 3-(hydroxymethyl)quinoline.

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“…This procedure was found as effective as the use of ß-glucuronidase. 7 In all the analyses OA served as a standard.…”

Section: Methodsmentioning

confidence: 99%

Pharrnacokinetics of nalidixinic acid and oxolinic acid in healthy wornen

Männistö

1976

Clin Pharma and Therapeutics

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The pharmacokinetics of oral nalidixic acid (NA, 1 gm 4 times a day) and oxolinic acid (OA, 750 mg 2 times a day) administered for 7 days were studied in the same 10 healthy women on the first, third, and seventh days of the treatment. The peak concentrations of NA + OH-NA (hydroxynalidixinic acid) in serum at 2 to 3 hr were 34 mug/ml (total) and 23 mug/ml (unconjugated) on the first day and nearly two times higher on the third and seventh days; 82% to 85% of these amounts were NA. The protein-free fraction of NA + OH-NA was 8.8% to 18.3%. The total concentration of NA + OH-NA in urine was 1,220 to 2,700 mug/ml, the unconjugated concentration, 250 to 350 mug/ml, and the chemotherapeutically active concentration, 55 to 75 mug/ml. In steady state the 24-hr recovery of the total drug was 79% of the daily dose. The excretion rate in urine was 591 to 853 mg/6 hr. The OA concentration in serum was very low on the first day of the treatment, but increased to 4- to 5-fold on the third and seventh days: 6.2 to 6.4 mug/ml (total) and 3.3 to 3.6 mug/ml (unconjugated). The protein-free OA represented 19% to 23% of the total amount. The modest initial serum concentrations of OA were confirmed by the low urine concentrations on the first day. In steady state the OA concentration in urine was 570 mug/ml (total) and 35 mug/ml (unconjugated), and the 24-hr recovery, 49% and 3%, respectively. The microbiologic assay gave somewhat higher concentrations of the active drug than did the chemical assay. When taken with food, the excretion of OA in urine was retarded by 6 hr but the 48-hr recovery was not decreased.

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Biotransformation of the methylenedioxy moeity of oxolinic acid in man

Cited by 20 publications

References 6 publications

Pharmacokinetics of a novel quinolone, AT-4140, in animals

Pharmacokinetics of a novel quinolone, AT-4140, in animals

Transformation of cinoxacin byBeauveria bassiana

Pharrnacokinetics of nalidixinic acid and oxolinic acid in healthy wornen

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