Pharmacokinetics and tissue distribution after intravenous administration of a single dose of amphotericin B cochleates, a new lipid-based delivery system.
Model independent pharmacokinetic analysis of intravenous (iv) amphotericin B cochleates (CAMB), a new lipid-based drug delivery system, in mice (0.625 mg/kg) shows a two-phase disposition profile in blood [area under the curve of concentration versus time from time zero to infinity (AUC(0-infinity)) = 1.01 microg. h/mL, half-life (t((1/2))) = 11.68 h, volume of distribution at steady state (V(ss)) = 9.59 L/kg, clearance (CL) = 10.36 mL/min/kg and mean residence time from time 0 to infinity (MRT(0-infinity)) = 15.41 h). In target tissues, maximum time (t(max)) ranged from 2 min (spleen and lung) to 10 min (liver) and lungs presented the highest AMB concentration (16.4 microg. h/g) followed by liver (8.56 microg/g), and spleen (6.63 microg/g). In addition, liver and spleen presented the longest elution half-life (75.03 and 66.71 h, respectively), MRT(0-infinity) (98.4 and 86.3 h, respectively), and AMB exposure:liver AUC(0-infinity) = 474 and 116.4 microg. h/g for the spleen. The large V(ss) and the extensive tissue AUC indicate large and efficient ability of cochleates to penetrate and deliver AMB. Differences in tissue uptake mechanism and pharmacokinetic data suggest a crucial role of macrophages in CAMB clearance from blood as well as an essential role of the liver and the spleen in AMB distribution to target tissues.
Segarra
Ignacio
I
BioDelivery Sciences International, Department of Biopharmacy and Pharmacokinetics, UMDNJ, New Jersey Medical School, 185 South Orange Avenue, Building 4, Newark 07103, USA.
Movshin
Diane A
DA
Zarif
Leila
L
D000042:Absorption; D000666:Amphotericin B / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D003840:Deoxycholic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D004338:Drug Combinations; D016503:Drug Delivery Systems; D006207:Half-Life; D007202:Indicators and Reagents; D007275:Injections, Intravenous; D008055:Lipids; D051379:Mice; D008810:Mice, Inbred C57BL; D014018:Tissue Distribution
D000935:Antifungal Agents; D004338:Drug Combinations; D007202:Indicators and Reagents; D008055:Lipids; D003840:Deoxycholic Acid; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination