Pharmacokinetics of MDL 63,246, a new semisynthetic glycopeptide antibiotic, in the rat
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M Borgonovi1, L A Cavenaghi, A Borghi
1Lepetit Research Center, Marion Merrell Dow Research Institute, Gerenzano (Varese), Italy.
Abstract:
Following intravenous administration in the rat, the concentration of MDL 63,246 in plasma was high and long-lasting. Concentrations fell with an apparent three-exponential decay. MDL 63,246 was distributed in a high volume and was cleared quite slowly. The pharmacokinetics of MDL 63,246 in the rat appear to be dose proportional in the dose range of 20 to 50 mg/kg of body weight. When administered subcutaneously, MDL 63,246 was slowly absorbed from the injection site, and the extent of availability was good, being 70.1%. MDL 63,246 was eliminated slowly by both renal and fecal excretion. MDL 63,246 is rapidly and extensively distributed into the tissues. At 0.5 h after drug administration, radioactivity was detected in all organs examined. At 24 h after administration, the total concentrations of radioactivity still increased in some organs which represent a slowly equilibrating compartment, but only the kidneys and liver showed a higher total concentration of radioactivity than plasma. Between 24 and 192 h after treatment, total concentrations of radioactivity decreased very slowly, and finally, apart from brain, all tissues showed higher concentrations than plasma, indicating a very high affinity of MDL 63,246 for tissues. The ratio of the concentration of radioactivity in blood to that in plasma ratio was 0.58, indicating that MDL 63,246 does not diffuse into erythrocytes and that binding to the erythrocyte membrane does not occur. All of these findings appear to correlate with the excellent in vitro and in vivo activities of the compound, suggesting that MDL 63,246 could be therapeutically efficacious at lower dosages and longer treatment intervals than those currently used for vancomycin and teicoplanin.
Insights
MDL 63,246 exhibits prolonged plasma concentrations and extensive tissue distribution in rats, suggesting potential for improved therapeutic efficacy compared to vancomycin and teicoplanin.
Area of Science:
- Pharmacology and Drug Metabolism
- Toxicology
- Medicinal Chemistry
Background:
- Understanding the pharmacokinetic profile of novel antimicrobial agents is crucial for optimizing therapeutic strategies.
- Existing treatments like vancomycin and teicoplanin have limitations that necessitate the development of alternatives.
Purpose of the Study:
- To characterize the pharmacokinetic properties of MDL 63,246 following intravenous and subcutaneous administration in rats.
- To evaluate the tissue distribution and elimination pathways of MDL 63,246.
- To compare the potential therapeutic utility of MDL 63,246 with current standards of care.
Main Methods:
- Intravenous and subcutaneous administration of MDL 63,246 in rats.
- Plasma and tissue concentration measurements using radioactivity detection.
- Pharmacokinetic parameter analysis including decay rates, volume of distribution, and clearance.
- Assessment of dose proportionality and bioavailability.
Main Results:
- MDL 63,246 demonstrated high and long-lasting plasma concentrations with a three-exponential decay after IV administration.
- The drug exhibited a large volume of distribution and slow clearance, with dose-proportional pharmacokinetics between 20-50 mg/kg.
- Subcutaneous administration resulted in slow absorption and good bioavailability (70.1%), with slow elimination via renal and fecal routes.
- Extensive and rapid tissue distribution was observed, with high tissue concentrations persisting for up to 192 hours, indicating strong tissue affinity.
- MDL 63,246 did not diffuse into erythrocytes, suggesting no significant binding to erythrocyte membranes.
Conclusions:
- MDL 63,246 possesses favorable pharmacokinetic properties, including sustained plasma levels and extensive tissue distribution.
- The drug's pharmacokinetic profile and high tissue affinity suggest potential for enhanced therapeutic efficacy.
- MDL 63,246 may allow for lower dosages and longer treatment intervals compared to vancomycin and teicoplanin.