Protein binding of glycopeptide antibiotics with diverse physical-chemical properties in mouse, rat, and human serum.

In previous studies of the pharmacokinetics and urinary excretion of nine glycopeptides with diverse isoelectric points (pI), as pI decreases, the total systemic and renal clearance, urinary recovery, and volume of distribution decrease, whereas the half-life increases. With glycopeptides of similar pI, clearance decreases and half-life increases with increasing lipophilicity. The present study examines the serum protein binding of these glycopeptide antibiotics in mouse, rat, and human serum and calculates the previously reported pharmacokinetic parameters for these drugs based on unbound concentration. Increased negative charge and lipophilicity increase serum protein binding (90-fold, fu 83% to 0.96%), which decreases the renal clearance and total systemic clearance (90-fold, 16.4 to 0.18 ml/min/kg) of these drugs. Increased serum protein binding also decreases the volume of distribution of these compounds, but this change is relatively small (sixfold, 755 to 131 ml/kg) compared with the change in total systemic clearance causing an increase in elimination half-life (25-fold, 20 to 492 min). The results demonstrate that the large differences in the total systemic clearance and half-life of these glycopeptide antibiotics are primarily due to dramatic differences in serum protein binding and not to differences in the intrinsic elimination processes (enzymes or transport proteins). It appears that the same physical-chemical properties that govern the protein binding and pharmacokinetics of small organic molecules govern the disposition of these high-molecular weight glycopeptide antibiotics.

Pharmacokinetics of dopamine-2 agonists in rats and dogs.

The absorption, protein binding, blood-to-plasma ratio, renal excretion, and pharmacokinetics of the dopamine-2 agonists (D2-agonists) 4-(2-di-n-propylaminoethyl)-7-hydroxy-2-(3H)-indolone (1), N-(2'-hydroxy-5'-[N,N-di-n-propylaminoethylphenyl])methanesulfonamide (2), and 4-(2-di-n-propylaminoethyl)-2-(3H)-indolone (3) were examined in dogs and rats. On the basis of relative cumulative urinary recoveries of radiolabeled drug, all three compounds are well absorbed in rats and dogs. In dogs, the free fractions in plasma of unchanged 1, 2, and 3, determined by in vitro studies, were 74, 86, and 63%, respectively, and the protein binding was constant with increasing concentration. The blood-to-plasma partition ratios of the respective compounds were 1.22, 1.14, and 1.16 in dogs, and the ratios were constant with increasing concentration. Large differences between species (dogs, rats, and humans) in protein binding and blood-to-plasma ratios were not seen. The clearances (blood or plasma) of 1 and 2 in dogs were significantly greater than the clearance of 3. The clearance of 3 was almost exclusively nonrenal, whereas 13% of 1 and 2 were recovered unchanged in urine. The steady-state volumes of distribution and the distribution and elimination half-lives of the three compounds were not significantly different. Importantly, the mean residence time of 3 (147 min) in dogs was significantly longer than those of 1 (90 min) and 2 (96 min). The results of analogous studies in rats indicate that 1 and 2 are more rapidly metabolized than 3.

Distribution in normal and inflammatory tissue of a new semisynthetic cephalosporin, SK&F 75073.

SK&F 75073 is a new cephalosporin with broad spectrum antibacterial activity. SK&F 75073-14C and cefazolin-35S were administered separately to groups of rats as a single intramuscular dose of 20 mg/kg. Tissues with highest drug levels 15 minutes following dose were as follows: (SK&F 75073/cefazolin levels), kidney - 86/70 microgram/g, liver - 33/22 microgram/g, lung - 29/17 microgram/g, heart - 23/10 microgram/g, adrenal - 13/7 microgram/g. Plasma levels at peak were 134 microgram SK&F 75073/ml (half-life, 1.9 hours) and 72 microgram cefazolin/ml (half-life, 0.75 hours). Dose excreted in 24 hours was: SK&F 75073, urine 66% and feces 27%; cefazolin, urine 96% and feces 2%. Both antibiotics were also administered, at 20 mg/kg, to rats with the carrageenan-induced inflammatory pouches. Exudate from these pouches contained from 2 to 10 times more SK&F 75073 than cefazolin. Radioassay and bioassay of these substances in the exudate gave similar results. Serum protein binding ranged from 96 approximately 98% for SK&F 75073 and 34 approximately 69% for cefazolin. Data indicated that highly protein bound SK&F 75073 enters tissues and tissue fluid to a greater extent than the lesser bound but therapeutically proven antibiotic agent cefazolin.

Use of anemic piglet to assess bioavailability of iron from oral iron preparations.

Except for methods using long-lived iron isotopes, there are no reliable means for assessing the bioavilability of iron from oral preparations in human subjects. Use of the anemic piglet as an alternative means was studied. When piglets were made anemic on a commercial milk diet and then dosed with solutions of 1, 2, and 5 mg/kg of ferrous sulfate/day, a dose-related recovery of hematocrit and hemoglobin levels resulted. The most sensitive dose range for use in a bioavailability study of iron was between 1 and 2 mg of iron/kg/day when using these parameters. A study carried out using this method indicated that the iron from a delayed-release capsule and from a ferrous sulfate solution was equally bioavailable. Hemoglobin and hematocrit recovery rates of the anemic piglet were shown to be reliable and sensitive indicators of the bioavailability of iron from various iron dosage forms.