Postnatal development of carrier-mediated absorption of a foreign amino acid from the rat lung.

To investigate the postnatal development of the carrier-mediated transport process by which certain amino acids are absorbed from the air space of the lung into the blood-stream, a solution of the 14C-labeled nonmetabolized amino acid cycloleucine was administered into the lungs of anesthetized rats of various ages and the rate of absorption of the compound measured. Carrier transport was barely detectable in animals 3-6 days of age; it increased markedly by th age of 12 days, and it reached nearly mature levels by 18 days of age. The rate of development of this carrier process was considerably slower than that previously reported for the organic anion carrier system of the rat lung.

Effect of papain-induced emphysema on permeability of rat lung to drugs.

To investigate the effect of a papain-induced emphysema-like condition on pulmonary absorption of drugs, rats were exposed to either papain aerosol or distilled water aerosol (control) intermittently for 2 wk, and rates of drug absorption from damaged and control lungs were compared. To measure absorption rates, 0.1 ml of drug solution (0.1-10 mM) was administered through a tracheal cannula to anesthetized animals, and after various times lungs were assayed for unabsorbed compound. In absorption experiments with the lipoid-insoluble compounds, mannitol, p-aminohippuric acid, and procaine amide ethobromide, all three drugs were absorbed from the lungs about twice as rapidly in papain-treated rats as in control. In contrast, procaine amide, a relatively lipoid-soluble drug, was absorbed at the same rate in both control and papain-treated animals. The results suggest that papain-induced lung damage increases the porosity of the pulmonary epithelium.

Enhanced pulmonary absorption of drugs in rats with experimental silicosis.

To investigate the effect of pulmonary silicosis on absorption of drugs from the lung, rats were given an intratracheal injection of 50 mg quartz dust, and rates of drug absorption from silicotic and control lungs were compared at 60 and 120 days after treatment. The pulmonary absorption of procaine amide ethobromide and p-aminohippuric acid was increased by 33-41% in animals with silicosis, whereas absorption of procaine amide in silicotic animals was not significantly different from control. The results suggest that silicosis results in an increased porosity of the pulmonary epithelium.

Lung pH and pulmonary absorption of nonvolatile drugs in the rat.

The effect of pH on pulmonary absorption of nonvolatile drugs was investigated in the rat. Krebs-Ringer phosphate solutions (pH 6.2 and 7.4), Krebs-Ringer pyrophosphate solution (pH 8.4), or an unbuffered salt solution containing a drug were administered through tight-fitting tracheal cannulas to anesthetized animals. After 3 min, the lungs were removed and assayed for the amount of drug that remained. Weak acids and a weak base were absorbed most rapidly at pH values at which the drugs were least ionized. For example, with the base procainamide, 36% of the dose was absorbed at pH 6.2 and 76% at pH 8.4. With the acid sulfisoxazole, 71% was absorbed at pH 6.2 and 55% at pH 8.4. Similarly, with p-aminosalicylic acid, 77% was absorbed at pH 6.2 and 40% at pH 8.4. In contrast to these results, compounds such as urea and amitrole, which remain completely nonionized over the pH range studied, showed no change in absorption rate when the pH was varied. The two weak acids and the weak base were absorbed from an unbuffered solution as though the pH at the site of drug absorption was between 6.2 and 7.4. The absorption rate for each weak electrolyte from unbuffered solution, when compared graphically with the respective absorption rates from buffered solutions, indicated that the pH at the site of drug absorption is about 6.6.

Effect of paraquat-induced lung damage on permeability of rat lung to drugs.

To investigate the effect of paraquat-induced lung damage on pulmonary absorption of drugs, rats were given a single oral dose of paraquat (250 mg/kg), and rates of drug absorption from damaged and control lungs were compared after various times. To measure absorption rates of drugs, 0.1 ml of 10 mM drug solution was administered through a tracheal cannula to anesthetized animals and, after various times, lungs were assayed for unabsorbed compound. Drugs investigated were procaine amide ethobromide, p-aminohippuric acid, and procaine amide. Rates of drug absorption increased 1.4-2.8-fold at 3.5 days after paraquat administration and returned to near control values by the 15th day. The results suggest that paraquat-induced lung damage increases the porosity of the pulmonary epithelium.

Active transport of phenol red by rat lung slices.

32S-phenol red was taken up by rat lung slices incubated in oxygenated Krebs-Ringer phosphate-glucose solution (pH 7.4) at 37 degrees C by a process showing the characteristics of active transport. Uptake against a concentration gradient occurred by a saturable process that was inhibited by low temperature, anaerobic conditions and certain metabolic inhibitors. Phenol red uptake was depressed in the presence of certain anionic dyes, such as chlorphenol red, bromphenol blue, bromthymol blue and bromcresol green, and by various other organic acids, including disodium cromoglycate, probenecid, cephalothin and benzylpenicillin. In contrast, isoniazid and p-aminohippuric acid had no effect on phenol red uptake, suggesting that a specificity exists in the rat lung for transport of anionic compounds. Interestingly, in the presence of paraquat, an organic cation,phenol red uptake was increased. The extent of uptake of phenol red by lung slices was dependent on levels of Na, K and Ca ion in the incubation medium as well as on the thickness of the tissue slice. Phenol red was bound to lung homogenates; however, the characteristics of the binding were such that binding alone could not account for accumulation by lung slices.

Effect of oxygen toxicity and nitric acid-induced lung damage on drug absorption from the rat lung.

To investigate the effect of pulmonary oxygen toxicity and nitric acid-induced lung damage on absorption of drugs from the lung, rats were either exposed continuously to approximately 100% oxygen or given an intratracheal injection of 1% nitric acid solution (0.15 ml), and rates of drug absorption from damaged and control lungs were compared after various times. To measure pulmonary absorption rates, 0.1 ml of drug solution (0.1-10 mM) was administered through a tight-fitting tracheal cannula to anesthetized animals, and, after various times, lungs were assayed for unabsorbed drug. Drugs investigated were procaine amide ethobromide, p-aminohippuric acid, procaine amide and mannitol-14C. Rates of drug absorption were increased 1.1-1.2 fold after 48-54 hrs of continuous oxygen exposure and 1.3-1.6 fold at 1-4 days after nitric acid treatment. The results suggest that both types of lung damage increase the porosity of the absorbing membrane, and that nitric acid damage also alters the integrity of lipoid regions of the membrane.

Pulmonary absorption of amino acids in the rat: evidence of carrier transport.

To investigate the absorption of nonmetabolized amino acids from the rat lung, 0.1 ml of Krebs-Ringer phosphate solution containing either 14C-labeled 1-aminocyclopentanecarboxylic acid (cycloleucine) or alpha-aminoisobutyric acid (AIB) was administered to anesthetized animals by way of a catheter introduced through a tight-fitting tracheal cannula. After various times, lungs were removed and assayed for the amount of amino acid that remained. Cycloleucine appeared to be absorbed by a combination of at least two processes: saturable carrier-type transport and a nonsaturable process. The saturable process was inhibited to varying degrees by a number of L- and D-amino acids but not by D-ornithine, betaine, 3-O-methyl-D-glucose, phenol red, disodium cromoglycate, or tetraethylammonium. The nonsaturable process appeared to be too rapid to be accounted for by diffusion alone, thus suggesting interaction with a second carrier system of high capacity. Although AIB was a weak inhibitor of cycloleucine transport, it appeared to be absorbed solely by a nonsaturable process at a rate consistent with diffusion through aqueous membrane channels.

Effect of cortisone on permeability of the neonatal rat lung to drugs.

The effect of cortisone (5 mg/animal i.p. on day 5 after birth) on the development of adult-type permeability characteristics in the lung was investigated in rats 6-18 days of age. In both treated and control rats, the lipid-soluble drug procainamide was absorbed at similar rates in all age groups. In contrast, in cortisone-treated animals, pulmonary absorption rates for the lipid-insoluble compounds mannitol and p-aminohippuric acid declined to adult levels at the age of 6 days, which was 12 days earlier than in controls. Cortisone treatment thus accelerates development of adult permeability characteristics in the pulmonary epithelium.

Transport of choline out of the cranial cerebrospinal fluid spaces of the rabbit.

The role which carrier-mediated transport and passive diffusion play in the clearance of quaternary ammonium compounds from cerebrospinal fluid was evaluated by ventriculocisternal perfusion in rabbits by using [14C]choline as the primary test compound. Choline was transported out of cerebrospinal fluid by two processes: a saturable, carrier-mediated process with a Tmax of 70.5 ng/min and Kt of 2.2 microgram/min; and, a passive nonsaturable process with a cerebrospinal fluid perfusate clearance of 11.5 microliter/min. N1-methylnicotinamide depressed the clearance of choline as well as that of hexamethonium, suggesting that these cations share a common transport process. Ouabain reduced the clearance of choline and hexamethonium. Passage of choline into brain occurred by passive diffusion.

Absorption of aerosolized drugs from the rat lung.

To investigate the absorption of aerosolized drugs from the rat lung, anesthetized animals were allowed to inhale through a tracheal cannula liquid aerosols of drug solutions generated with an air-jet nebulizer. The aerosols had a mass median aerodynamic diameter of 2.81 +/- 0.08 micron and a geometric standard deviation of 2.53 +/- 0.05. At various times after aerosol inhalation, the lungs were removed and assayed for the amount of compound that had not been absorbed. The times (min) necessary for 50% absorption were: antipyrine, 0.25; salicylic acid, 0.67; barbital, 0.93; amitrole, 1.3; urea, 1.4; procainamide, 2.3; guanidine, 3.1; erythromycin, 6.3; benzylpenicillin, 20.5; p-aminohippuric acid, 21.7; mannitol, 26.5; and N-acetylprocainamide ethobromide, 34.5. Comparison with previously reported absorption rates measured after intratracheal injection of 0.1 ml of drug solution showed that drug inhaled as an aerosol was absorbed roughly two times more rapidly than when administered by intratracheal injection. The results suggest that drug absorption may be more rapid from the alveolar region than from the tracheobronchial region of the lung.

Pulmonary absorption of drugs in the neonatal rat.

To compare the pulmonary absorption of drugs in newborn rats (3-27 days old) with that in adults, 0.01-0.1 ml of Krebs-Ringer phosphate solution (pH 7.4) containing a drug was administered to anesthetized animals by way of a catheter introduced through a tight-fitting tracheal cannula. After various times, lungs and trachea were removed and assayed for drug that remained. Semilogarithmic plots of percent drug remaining against time yielded a straight line for each compound. The lipid-soluble drugs procaine amide and sulfisoxazole were absorbed at similar rates in newborn and adult rats. In contrast, the lipid-insoluble drugs tetraethylammonium, p-aminohippuric acid, and mannitol were absorbed approximately 2 times more rapidly in younger rats (3-12 days) than in older animals (18 day, 27 day, or adult). The results suggested that the respiratory tract membranes of 3- to 12-day-old rats have a greater porosity than those of older animals.

Effect of thyroxine on permeability of the neonatal rat lung to drugs.

The effect of thyroxine (1-2 microgram/g i.p. on days 1-4 after birth) on development of adult-type permeability characteristics in the lung was investigated in rats 6-18 days of age. In both treated and control rats, the lipid-soluble drug procaine amide was absorbed at similar rates in all age groups. In contrast, in thyroxine-treated animals, pulmonary absorption rates for the lipid-insoluble compounds mannitol and p-aminohippuric acid declined to adult levels at age 6-12 days, 6 days earlier than in controls. Thyroxine treatment thus accelerates development of adult permeability characteristics in the pulmonary epithelium.

Binding of organic compounds to rat liver and lung.

The binding of various radioisotopically labeled organic compounds to rat liver and lung was investigated in vitro. Pieces of rat lung and slices of rat liver were incubated at 37 degrees C under a nitrogen atmosphere in a modified Krebs-Ringer phosphate solution (pH 7.4) CONTAININg the compound to be studied. Of the neutral compounds investigated, digitoxin, digoxin and dexamethasone were highly bound to both liver and lung tissue, whereas the degree of binding of amitrole, erythritol, and ouabain was 20% or less. The weak acids which were bound to the greatest extent in both liver and lung were phenobarbital, pentobarbital, and diphenylhydantoin. Barbital was poorly bound, and there was no evidence for the binding of 5,5-dimethyloxazolidine-2,4-dione or p-aminohippuric acid in either tissue. Binding of the cardiac glycosides and the barbiturates directly paralleled their lipid solubilities. The degree of binding of neutral compounds and weak acids to lung and liver tissue did not vary greatly with concentration, even though broad concentration ranges were studied. This was also true of the weak base morphine. On the other hand, the binding to liver and lung of the organic bases nicotine, pilocarpine, d-amphetamine, lidocaine, erythromycin, and chloroquine, did vary with concentration. The quaternary ammonium compound decamethonium was bound only to liver, and this binding also varied with concentration. Two additional quaternary ammonium compounds, tetraethylammonium and N1-methylnicotinamide, were not significantly bound to either tissue. Comparisons on the basis of equal content of solids revealed that the binding of diverse organic compounds in liver is greater than or equal to that in lung.