Pharmacokinetics of iodamide in normal subjects and in patients with renal impairment.

The pharmacokinetic characteristics of iodamide, a contrast agent for excretion urography, were studied in seven normal subjects and in 15 patients with various degrees of renal impairment. Two different formulations were administered, namely, a 65% solution (iodamide 300) by slow intravenous injection and a 24% solution by slow intravenous (drip) infusion. Both preparations of iodamide exhibited characteristics of an open two-compartment model. In both normal subjects and patients, the contrast agent was excreted almost exlusively in urine. In normal subjects, the pharmacokinetic parameters of both formulations were similar, with a distribution half-life (1/2alpha) of about 3 minutes and a disposition half-life (t1/2beta) of about 69 minutes. An average of 84 per cent of the dose was excreted in urine within 4 hours after administration of iodamide with net renal tubular secretion of about 38 per cent. The binding of iodamide to plasma proteins was negligible, and the extent of biotransformation of iodamide was minimal. In patients with renal impairment, the disposition half-life (t1/2beta) of iodamide ranged from 4.1 to 16.4 hours. Other changes in pharmacokinetic parameters were also seen in patients with renal impairment.

Fluorometric determination of cephradine in plasma.

A fluorometric method was developed for the determination of cephradine in plasma. A fluorescent product is formed when samples of deproteinized plasma containing cephradine are heated for 3 hr at 100 degrees and pH 1. The fluorescence is determined in sodium hydroxide solution (pH 13.5) at excitation and emission wavelengths of 350 and 445 nm, respectively. Only 0.1 ml of plasma is required, and concentrations of cephradine as small as 0.1 mug/ml may be determined. In plasma samples from a dog taken over a 10-hr period after an intramuscular injection of 250 mg of cephradine, essentially similar concentrations of cephradine were obtained by the fluorometric method and a standard microbiological bioassay.

Protein binding of drugs.

Basic considerations involved in the interaction of drugs with proteins are reviewed. The important role of the concentration of unbound drug in determining therapeutic and toxicologic effects is emphasized. Ultra-filtration is suggested to be the method of choice for the determination of concentrations of unbound drug in plasma in clinical practice.

Pharmacokinetics of cephalosporin antibiotics: protein-binding considerations.

The therapeutic activity of antibiotics depends on several factors including absorption, elimination kinetics, distribution in the body, minimal inhibitory concentrations (MIC), stability against enzymes, and plasma-protein binding. Some of these factors are interrelated, for example, the extent of protein binding of an antibiotic influences its elimination kinetics, distribution into tissues, MIC, and antibacterial activity. To evaluate the potential efficacy of an antibiotic, it is important to know the extent of its binding to plasma proteins especially since the protein-bound fraction of the antibiotic is devoid of antibacterial activity. Cephalosporins are a new class of broad-spectrum antibiotics that bind to plasma proteins in different degrees. Reported values for protein binding range from 6% for cephradine to 92% for cefazolin. The effects of protein binding of some of the commonly used cephalosporins on antibacterial activity and several pharmacokinetic parameters are discussed in this communication.

Metabolism of tracazolate. Metabolites in dog and rat urine.

The urinary metabolites of tracazolate [4-n-butylamino-1-ethyl-6-methyl-1H-pyrazolo (3,4-b) pyridine-5-carboxylic acid ethyl ester], an anxiolytic agent, obtained from rats and dogs dosed with 14C-labeled tracazolate have been characterized. No unchanged tracazolate was detected. Fifteen metabolites were identified in dog urine, seven of which had not previously been found in rat blood and tissue. Eleven of these metabolites were also found in rat urine. The metabolites were formed by deesterification to the 5-carboxylic acid; N-deethylation of the pyrazole ring: oxidation at the gamma-position of the n-butylamino side chain; oxidation of the terminal carbon of this side chain; loss of the n-butylamino group; and hydroxylation of the 6-methyl group followed by condensation with the 5-carboxylic acid to form gamma-lactones. The major metabolites in dog urine were the desethyl-desbutyl-deesterified compound, the desbutyl-deesterified compound, and the desbutyl-desethyl-lactone. Loss of the butyl side chain and, also, lactone formation, appeared to occur to a lesser extent in the rat than in the dog.

Tissue distribution of 14C- and 35S-captopril in rats after intravenous and oral administration.

35S-Captopril (50 mg/kg) administered i.v. to rats resulted in radioactivity being widely distributed into highly vascular tissues and into excretory organs. After oral administration of 14C-captopril (50 mg/kg), radioactivity in most tissues declined at a rate similar to that in blood. Concn. greater than those in blood were found only in kidney, liver and lung. The high concn. of 14C in kidney and liver were due to the excretory role of these organs. The high concn. of 14C in lung may be due to the high binding affinity of captopril to angiotensin-converting enzyme, present in large quantity in lung.

Distribution of captopril to foetuses and milk of rats.

1. 14C-Captopril (50 mg/kg) administered orally to pregnant rats resulted in radioactivity passing the placental barrier into foetuses and amniotic fluid. Two hours after dosing, the mean (+/- S.E.M.) concentration of total radioactivity was 0.97 +/- 0.07 micrograms equiv. of captopril/g in foetuses and 7.8 +/- 0.54 micrograms equiv./g in maternal blood. The mean concentration of unchanged captopril at this time was 0.22 +/- 0.04 micrograms/g in foetuses and 2.4 +/- 0.27 micrograms/g in maternal blood. Results obtained by whole-body autoradiography generally were consistent with those obtained by measuring radioactivity in excised tissues. 2. Radioactivity was also found in suckling pups and in the milk of th dams. Autoradiographs of the pups showed detectable radioactivity in the brain; as no radioactivity was detectable in the brain of the dam, it appears that the blood-brain barrier was not fully developed in seven-day-old pups.

Human serum protein binding of cephalosporin antibiotics in vitro.

The published values for serum protein binding of antibiotics vary considerably depending upon the method and experimental conditions used. A rapid, simple, and standardized ultrafiltration procedure for determination of the serum protein binding of antibiotics has been developed and used to compare the binding characteristics of four marketed cephalosporins. The human serum protein binding of cephradine, cephalexin, cephalothin, and cefazolin at 37 degrees C. and physiological pH (7.4) was found to be 13.8, 12.4, 71.2, and 89.2 per cent, respectively. These values fall within the range of published values for these antibiotics.