1. The plasma protein binding characteristics of ceftriaxone, a new cephalosporin antibiotic, were determined in human, baboon, rabbit, dog and rat plasma. 2. The protein binding of ceftriaxone was similar and concentration-dependent in human, baboon, rabbit and rat plasma, being highly bound (90-95%) at low concentrations (less than 100 micrograms/ml) but considerably less bound (approx. 60%) at high concentrations (greater than 400 micrograms/ml). Binding in dog plasma was also concentration-dependent but much lower (approx. 25%) at lower concentrations (30 micrograms/ml) and virtually unbound (2%) at high concentrations (1 mg/ml) over a similar concentration range. 3. Binding of ceftriaxone to human plasma involved two sites: a high affinity-low capacity (saturable) site and a low affinity-high capacity site. Binding to dog plasma apparently was at a single, high affinity-low capacity site. 4. The pharmacokinetics of ceftriaxone in an animal species with binding characteristics similar to man (baboon), appear to be non-linear when based on total drug concentration and linear when based on the free drug concentration. In the dog, pharmacokinetic parameters did not change appreciably if calculated from total or free drug concentrations, due to the low protein binding.
It has been shown that the antiarrhythmic and toxic effects of lidocaine may be in part dependent on its two active metabolites, monoethylglycylxylidide (MEGX) and glycylxylidide (GX). Presently available gas liquid chromatographic analytic methods require long and tedious steps or sophisticated equipment such as gas liquid chromatography-mass spectrometry. The assay method reported here with the use of high-performance liquid chromatography is rapid and allows accurate, precise determination of lidocaine, MEGX, and GX in biologic fluids. On the 3 patients studied extensively with the use of this assay, one patient had MEGX concentrations almost twice those of lidocaine. At 83% lidocaine potency, the contribution of MEGX in this patient was about 1.5 times that of lidocaine. The second patient studied on two consecutive days had a 20% increase in serum lidocaine concentration and an equivalent decrease in MEGX concentration on the second day. In the third patient lidocaine was stopped with a resulting half-life of 3.8 hr, which is consistent with previously reported values for patients on long-term lidocaine infusion. Urinary excretion of lidocaine and its metabolites is in agreement with previous work. These data suggest that much information still remains to be learned about the active metabolites of lidocaine as well as of lidocaine.
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