Pulmonary extraction and accumulation of lipid formulations of amphotericin B.
OBJECTIVE
To compare single-dose first pass uptake and accumulation of conventional amphotericin B (cAmB), liposomal amphotericin B (L-AmB), and amphotericin B lipid complex (ABLC) by the intact feline lungs.


METHODS
Prospective, controlled animal study.


METHODS
Experimental laboratory in a university teaching hospital.


METHODS
A total of 31 spontaneously breathing, anesthetized cats.


METHODS
The pulmonary uptake of cAmB, L-AmB, and ABLC during a single passage through the pulmonary circulation, and the pulmonary retention of these drugs were studied after a bolus [cAmB, L-AmB, and ABLC, 1 mg/kg (n = 9 each) and ABLC, 5 mg/kg (n = 4)] administration into the right ventricle. The amount of drug taken up by the lung during the first pass was measured from double indicator-dilution outflow curves. Animals were killed 30 mins (cAmB, n = 4; L-AmB, n = 4), 1 hr (cAmB, n = 5; L-AmB, n = 5; ABLC, n = 5), or 6 hrs (ABLC, 1 mg/kg, n = 4; 5 mg/kg, n = 4) after drug administration.


RESULTS
The first-pass uptake of cAmB, L-AmB, and ABLC (mean +/- sD) by the lung was 73%+/-5%, 69%+/-8%, and 82%+/-6% of the injected dose (1 mg/kg), respectively (p > .05). ABLC (1 mg/kg) exhibited prolonged retention in the lung; 23% and 15% of the injected dose of ABLC remained in the lung 1 hr and 6 hrs after its administration, respectively. In contrast, cAmB and L-AmB exhibited rapid back diffusion of the drug out of the lung. After 30 mins, only 4% of the administered cAmB and L-AmB remained in the lung and after 1 hr only 1% to 2% was retained. Increasing the dose of ABLC from 1 mg/kg to 5 mg/kg did not alter pulmonary extraction of the drug; however, compared with the lower dose (1 mg/kg), higher concentrations of the drug were found in the lung 6 hrs after its administration.


CONCLUSIONS
The results demonstrate a substantial extraction and accumulation of ABLC by the lung. This affinity for the lungs may have clinical implications for treating fungal infections that primarily involve the lung. Further studies are required to confirm the potential clinical relevance of these data.
Department of Anesthesiology and Critical Care Medicine, Hadassah University Medical Center, The Hebrew University of Jerusalem, Israel.
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Matot
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Pizov
D000666:Amphotericin B / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000704:Analysis of Variance; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D001784:Blood Gas Analysis; D002302:Cardiac Output / Q000187:drug effects; D002415:Cats; D002851:Chromatography, High Pressure Liquid; D004337:Drug Carriers; D006863:Hydrogen-Ion Concentration; D008081:Liposomes; D008168:Lung / Q000378:metabolism*; D014018:Tissue Distribution
D000935:Antifungal Agents; D004337:Drug Carriers; D008081:Liposomes; D000666:Amphotericin B