RT Journal Article
SR Electronic
T1 Effect of plasma protein binding on the uptake of methadone and diazepam in the isolated perfused rat lung.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 536
OP 542
VO 12
IS 5
A1 D L Roerig
A1 R R Dahl
A1 C A Dawson
A1 R I Wang
YR 1984
UL http://dmd.aspetjournals.org/content/12/5/536.abstract
AB The pulmonary uptake of the basic (pKa 9.1) lipophilic amine (methadone) and a nonbasic (pKa 3.4) lipophilic amine (diazepam) was compared in a single pass isolated perfused rat lung (IPL) preparation. The radiolabeled drugs were infused into the IPL for 10 min followed by a 30-min drug-free perfusion. If the perfusate (Krebs-Ringer bicarbonate buffer) contained 4.5% bovine serum albumin, the rapid and extensive uptake observed for methadone (32.4% of infused amount) was similar to that reported for other basic lipophilic amines. Uptake of the nonbasic diazepam was slight (3.4% of infused amount). These results are consistent with the idea that basic amines accumulate in lung tissues to a great extent. However, if the bovine serum albumin was omitted from the perfusate, diazepam uptake in the IPL increased about 10-fold while methadone uptake increased only slightly. This observation, together with the extensive binding of diazepam to plasma albumin, suggested that plasma protein binding was a major factor in limiting the pulmonary accumulation of this nonbasic lipophilic amine. Since many nonbasic drugs are known to have a high affinity for plasma albumin, the observed dependence of pulmonary drug accumulation on basicity of the amine may be related to the plasma protein binding as well as the characteristics of the interaction of amines with pulmonary tissue.