Charge and lipophilicity govern the pharmacokinetics of glycopeptide antibiotics.

The pharmacokinetics and urinary excretion of nine glycopeptide antibiotics with diverse pIs (3.8 to 8.5) and lipophilicities were studied. The disposition of the aridicin antibiotics and their hydrolysis products were examined in male CD-1 mice after subcutaneous and intravenous administration and compared with the disposition of teicoplanin, ristocetin, and vancomycin. The total systemic clearance, half-life, volume of distribution, and urinary excretion were highly correlated with pIs. In general, as the pI decreased, the clearance, urinary recovery, and volume of distribution decreased, whereas the half-life increased. With those glycopeptides that had similar pIs, clearance decreased and half-life increased with increasing lipophilicity. The urinary recovery of the glycopeptides decreased with decreasing pI and increasing lipophilicity. Because vancomycin (pI = 8.0) is cleared by glomerular filtration, increased binding to serum is the likely mechanism of reduced renal clearance for glycopeptides with low pIs. These results are consistent with previous findings concerning the correlation of physical-chemical properties and the drug disposition of small organic molecules. Results of these studies also indicate that desirable pharmacokinetic properties can be incorporated into glycopeptides through semisynthetic modifications.