On human biotransformation of some penicillins.

Urinary excretion of ampicillin, amoxicillin and oxacillin was studied in five healthy volunteers. Determinations were carried out by chemical methods (PC, TLC, spectrophotometry). Beside the parent compounds and their penicilloic acids, an alphaamino-substituted derivative was demonstrated. The total recovery of amoxicillin was nearly complete, recovery of ampicillin and oxacillin was about 50%. The combination of aminopenicillins with oxacillin did not alter significantly the excretion of the individual compounds.     

Color reactions for identification of nalidixic acid

Nalidixic acid (1) gives with 2-naphthol a yellow charge-transfer complex. The 7-methyl group of 1 condenses with vanillin (2) and Ehrlich's reagent (4) to the coloured (E)-benzylidene compounds 3 and 5. Treating 1 with thionyl chloride and subsequent reaction with aminopyrazolone (6) and sodium acetate leads to a mixture of trichloronalidixic acid (7) and its 3-carboxamide 8. The trichloromethyl group of 7 is converted with 6 in pyridine to form the amide 9. Nalidixic acid reacts with 1,3-dimethylbarbituric acid (10) in acetanhydride/acetic acid to yield the polymethine dyes 11-13, whose structures are confirmed by X-ray crystal structure analysis. The dyes 3 and 12 inhibit the growth of staphylococcus aureus and Escherichia coli, respectively.     

The effect of infinitesimal drug dilutions on the pharmacokinetics of nalidixic acid and atenolol.

1. Ten healthy subjects received two treatments: a single 1 g oral dose of nalidixic acid (NA) followed 1 h later by either an infinitesimal dilution of the drug (NA 7CH) or by succussed water which served as placebo. The study was repeated 18 months later in 10 different subjects. 2. A further 10 healthy subjects received three treatments: a single 100 mg oral dose of atenolol (AT) followed 3 h later by either placebo or a dilution of AT (AT 7CH) or of bisoprolol (BI 7CH). The homoeopathic preparations were administered by the sublingual route. 3. In the first NA experiment NA 7CH significantly shortened the elimination half-life of NA from 8.6 +/- 2.2 (placebo) to 6.4 +/- 1.6 h (NA 7CH). In the second NA experiment none of the pharmacokinetic parameters was modified significantly by the administration of NA 7CH. Neither AT 7CH nor BI 7CH modified the pharmacokinetics of AT.     

山柰苷的人肠内细菌生物转化研究

目的探讨人肠内细菌对中药罗汉果中山柰苷的生物转化。方法采用人肠内细菌与山柰苷共温孵培养的方法，通过色谱技术分离、纯化转化产物，应用谱学技术确定转化产物的结构。结果人肠内细菌转化山柰苷产生山柰酚3-O-α-L-吡喃鼠李糖苷(阿福豆苷)、山柰酚7-O-α-L-吡喃鼠李糖苷、山柰酚和对-羟基苯甲酸。结论山柰苷可被人肠内细菌进行生物转化。     

Pharmacokinetics of nalidixic acid associated with sodium citrate

A pharmacokinetic study of sachets containing nalidixic acid (0.66 g) associated with sodium citrate (3.75 g)--NSC--was carried out in 10 healthy volunteers in order to determine the influence of the urine alcalinization due to sodium citrate on the elimination of nalidixic acid (NA) and its 7-hydroxy (HNA) and 7-carboxy (CNA) derivatives. Urine alcalinization enhanced markedly the urinary excretion of HNA, but not of NA and CNA. The urinary concentrations of bacteriologically active compounds--NA + HNA--remained above five times their minimum inhibitory concentration for 10 h following each dose. After a 3-day treatment using NSC three times daily there was no significant accumulation of NA and derivatives in the plasma and no significant change in their kinetics. Finally, from a pharmacokinetic viewpoint, the daily administration of 3 sachets of NSC each containing 0.66 g of NA seems valuable in the treatment of urinary tract infections.     

Nalidixic acid prodrugs: Amides from amino acid ester and nalidixic acid

Amides from amino acid ester and nalidixic acid were synthesized. The solubility characteristics and partition coefficient of the compounds were studied. The hydrolysis of the compounds was studied in the simulated gastric fluid and simulated intestinal fluid. Some compounds showed better antibacterial activity than nalidixic acid.     

Toxicity and carcinogenicity studies of nalidixic acid in rodents

Toxicity and carcinogenicity studies of nalidixic acid, an antimicrobial agent used to treat bacterial infections of the urinary tract, were conducted in F344/N rats and B6C3F1 mice of each sex for 13 weeks or 2 years. In the 13-week studies, nalidixic acid was administered at dietary concentrations ranging from 1,000 to 16,000 ppm. Body weights of both rats and mice were reduced in the groups receiving diet containing 8,000 and 16,000 ppm, and feed consumption of rats in the highest treatment groups was approximately two-thirds that of controls. Degeneration of the germinal epithelium in the seminiferous tubules of the testis was observed in male rats that received 16,000 ppm; no other compound-related histopathologic effects were observed in either species. Two-year studies were conducted by feeding diets containing 0, 2,000, or 4,000 ppm nalidixic acid to groups of 50 rats and mice/sex/group. The average daily feed consumption was slightly reduced compared to control groups and resulted in approximate daily doses of 82 or 175 mg nalidixic acid/kg for low dose and high dose rats, and 220 or 475 mg/kg for low dose and high dose mice. Mean body weights of dosed rats and mice were lower than those of controls, except for groups of low dose female rats and male mice. The incidences of preputial gland neoplasms in dosed male rats and of clitoral gland neoplasms in dosed female rats were significantly increased compared to those in controls; responses in low dose groups were similar to those in high dose groups. There were decreased incidences of leukemia and mammary gland neoplasms in dosed female rats and of pituitary gland neoplasms in dosed male rats. Subcutaneous tissue fibrosarcomas were marginally increased in dosed male mice. There were no increased incidences of neoplasms in dosed female mice. Under the conditions of these studies, the dietary administration of nalidixic acid was carcinogenic for rats, causing preputial gland or clitoral gland neoplasms in males and females, respectively. The association of subcutaneous neoplasms with administration of nalidixic acid to male mice was equivocal.     

The contribution of human small intestine to chlorpyrifos biotransformation

Despite the oral intake is the major route of exposure to chlorpyrifos for the general population, few data are available on human intestine biotransformation. In this study the contribution of chlorpyrifos (CPF) metabolism in human small intestine was investigated in microsomes from duodenum (HDM) and ileum/jejunum (HS2M) from 11 individual donors. Samples were characterized for testosterone hydroxylated metabolite formation and CYP content quantification by means of Western blotting. The two methods gave consistent results, evidencing the presence of CY3A4 and its-related activity in 10/11 samples, among which one showed also the presence of CYP2C9. Analogously, although with high interindividual variability (about 10 fold), CPF bioactivation to chlorpyrifos-oxon (CPFO) was observed in 10/11 HDM: intrinsic clearance highest value was 0.75 pmol CPFO/(mg protein min μM). Detoxication to 3,5,6-trichloropyrin-2-ol formation was negligible. The comparison between HDM and HS2M indicates that most CPF bioactivation was confined in the duodenum, declining toward the distal ileum. Results suggest that following oral exposure, the small intestine CPF bioactivation, although much lower when compared to the total hepatic metabolism, could play a role in the pre-systemic CPF clearance, with CPFO transported into the lumen by the efflux P-glycoprotein and further metabolized by esterases.