Physicochemical properties, pharmacokinetics, and biodistribution of gadoteridol injection in rats and dogs.

RATIONALE AND OBJECTIVES: The physicochemical properties of gadoteridol, a macrocyclic nonionic gadolinium complex, were studied together with its pharmacokinetics and biodistribution in rats and dogs. METHODS: Studies in rats were conducted after single intravenous injections at 0.1 or 0.35 mmol/kg using 153Gd-labeled gadoteridol or with seven daily doses of 0.1 mmol/kg to examine the levels of residual gadolinium in organs. Nonradioactive biodistribution and excretion studies were performed in dogs following injection at 0.1 mmol/kg. RESULTS: After injection, the dose was rapidly cleared from rat blood and excreted such that more than 90% of the dose appeared in the urine within 4 hr of injection. At 7 and 14 days postinjection, only extremely low levels of gadolinium were observed in liver and bone; these levels were two to eight times lower than the levels reported after the injection of gadopentetate dimeglumine. CONCLUSION: The extracellular distribution and rapid urinary excretion of gadoteridol is in agreement with data obtained with other gadolinium-containing chelates used as intravascular magnetic resonance imaging contrast agents. Differences observed in the long-term retention of gadolinium between gadoteridol and gadopentetate dimeglumine were consistent with the reported greater in vivo resistance to transmetallation of gadolinium macrocycles compared with the linear gadolinium chelate molecules.

Recognition of the difficult airway in normal Nigerian adults (a prospective study).

Difficulty with laryngoscopy and intubation is known to be the most frequent cause of anaesthetic related deaths. Awareness of the possibility of difficulty would enable the anaesthetist to be adequately prepared. 57 "normal" adult patients were examined pre-operatively and at laryngoscopy using the Mallampatti (1985) and the Cormack (1984) classification respectively. The result showed that none of the patients was in the IV Mallampatti nor IV Cormack groups. Four patients with class III Mallampatti features were seen, two of which were classified Cormack III at laryngoscopy. Intubation failed in these two patients. The majority of patients were classified as Mallampatti class I (68.42%) and Cormack grade I (63.16%). This in effect demonstrates that in most "normal" patients laryngoscopy and intubation should be fairly easy.

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 [14C]aztreonam in rat tissue.

[14C]aztreonam was administered intramuscularly (50 mg/kg) to male and female rats. Groups of 10 rats (five male and five female) were sacrificed at 0.25, 2, 6, and 24 h after dosing. Blood and various tissues were removed from six rats (three male and three female) in each group for determination of total radioactivity and unchanged aztreonam by liquid scintillation counting and thin-layer radiochromatography. The remaining rats were prepared for whole-body autoradiography. Radioactivity was distributed rapidly to most tissues and was rapidly eliminated from blood into urine and bile. Concentrations of total radioactivity in kidney, liver, small and large intestines and their contents, and urinary bladder were higher than those in serum at all the times examined. Concentrations of unchanged aztreonam in serum, kidney, liver, and lung declined at about the same rate as did that of total radioactivity in the same tissues. The results of whole-body autoradiography essentially confirmed the results of the distribution of [14C]aztreonam as determined by liquid scintillation counting. No major differences between males and females were observed when concentrations in organs common to both were compared.

Disposition of [14C]aztreonam in rats, dogs, and monkeys.

[14C]aztreonam was administered as single 25-mg/kg doses to dogs (intravenously and subcutaneously) and monkeys (intramuscularly and intravenously) and as single 50-mg/kg doses (intramuscularly and intravenously) to rats. In rats and dogs, radioactive moieties were excreted primarily in urine; in monkeys, they were excreted about equally in urine and feces. Unchanged aztreonam accounted for 77 to 86% of the radioactivity excreted in the urine of rats, dogs, and monkeys; SQ 26,992, the metabolite resulting from hydrolysis of the monobactam ring, accounted for 10 to 15%; and minor, unidentified metabolites accounted for the remainder. In rats with cannulated bile ducts, about 15% of an intramuscular dose was excreted in bile in 24 h; the bile contained a greater percentage of metabolites than that found in urine. In dogs, the apparent elimination half-life of aztreonam in serum was 0.7 h after intravenous administration. Aztreonam and SQ 26,992 accounted for most of the radioactivity in the sera of dogs and monkeys. Serum protein binding of aztreonam and its metabolites ranged from 28 to 35% in dogs and from 49 to 59% in monkeys. In the three species studied, aztreonam was most extensively metabolized in monkeys; SQ 26,992 and other minor metabolites from monkey urine were tested and found to be devoid of any significant antimicrobial activity.

Distribution of aztreonam into fetuses and milk of rats.

Subcutaneous administration of [14C]aztreonam (150 mg/kg) to pregnant rats was followed by the appearance of radioactive moieties in fetuses and amniotic fluid. Concentrations of both total radioactivity and unchanged aztreonam in maternal serum declined more rapidly than those in fetuses and amniotic fluid. [14C]aztreonam (150 mg/kg) was also administered subcutaneously to lactating rats. Radioactivity and unchanged aztreonam were found in the suckling pups and in the serum and milk of the dam. Results obtained by whole-body autoradiography were generally consistent with these obtained by measuring radioactivity present in the excised tissues. Autoradiographs of the pups showed detectable amounts of radioactivity in the brain; since no radioactivity was detectable in the brain of the dam, it appears that the blood-brain barrier was not fully developed in 7-day-old pups.

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.

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.