Comparison of plasma and interstitial fluid concentrations of doxycycline and meropenem following constant rate intravenous infusion in dogs

Objective-To compare plasma (total and unbound) and interstitial fluid (ISF) concentrations of doxycycline and meropenem in dogs following constant rate IV infusion of each drug. Animals-6 adult Beagles. Procedure-Dogs were given a loading dose of doxycycline and meropenem followed by a constant rate IV infusion of each drug to maintain an 8-hour steady state concentration. Interstitial fluid was collected with an ultrafiltration device. Plasma and ISF were analyzed by high performance liquid chromatography. Protein binding and lipophilicity were determined. Plasma data were analyzed by use of compartmental methods. Results-Compared with meropenem, doxycycline had higher protein binding (11.87% [previously published value] vs 91.75 +/- 0.63%) and lipophilicity (partition coefficients, 0.02 +/- 0.01 vs 0.68 +/- 0.05). A significant difference was found between ISF and plasma total doxycycline concentrations. No significant difference was found between ISF and plasma unbound doxycycline concentrations. Concentrations of meropenem in ISF and plasma (total and unbound) were similar. Plasma half-life, volume of distribution, and clearance were 4.56 +/- 0.57 hours, 0.65 +/- 0.82 L/kg, and 1.66 +/- 2.21 mL/min/kg, respectively, for doxycycline and 0.73 +/- 0.07 hours, 0.34 +/- 0.06 L/kg, and 5.65 +/- 2.76 mL/min/kg, respectively, for meropenem. The ISF half-life of doxycycline and meropenem was 4.94 +/- 0.67 and 2.31 +/- 0.36 hours, respectively. Conclusions and Clinical Relevance-The extent of protein binding determines distribution of doxycycline and meropenem into ISF As a result of high protein binding, ISF doxycycline concentrations are lower than plasma total doxycycline concentrations. Concentrations of meropenem in ISF can be predicted from plasma total meropenem concentrations.