Pulmonary absorption of drugs in the dog: comparison with other species.

To investigate the pulmonary absorption rate of drugs in the anesthetized beagle dog, 5 ml of drug solution was administered into the lungs by rapid injection through a tracheal cannula. After various times, lungs were removed and assayed for unabsorbed drug. The dog absorbed lipid-insoluble drugs such as p-aminohippuric acid, mannitol, and procainamide ethobromide at the same rate as the rat, two times more rapidly than the rabbit, and approximately 2-3 times more slowly than the mouse and guinea pig. In contrast, the dog absorbed a lipid-soluble drug like procainamide at the same rate as the other four species. The results suggest that pulmonary absorption rates measured in small laboratory animals can be used to predict absorption rates in large animals.

Species comparison of drug absorption from the lung after aerosol inhalation or intratracheal injection.

To compare the rates of pulmonary absorption of aerosolized and intratracheally injected drugs in the mouse, rabbit, and rat, anesthetized mice and rabbits prepared with a tracheal cannula inhaled a liquid aerosol or received an intratracheal injection of a drug solution by methods previously used in studies on the rat. Aerosols had mass median aerodynamic diameters in the range of 2.28-3.10 microm and geometric standard deviations in the range of 2.35-2.81. The volumes of solution injected intratracheally were approximately 2% of lung volume. At various times after drug administration, the lungs were removed and assayed for unabsorbed compound. Although the 12 drugs studied had widely different absorption rates, each was absorbed approximately 2 times more rapidly when inhaled as an aerosol than when administered by intratracheal injection, suggesting that absorption may be more rapid from the alveolar region than from the tracheobronchial region of the lung. With lipid-insoluble drugs, such as urea, benzylpenicillin, p-aminohippuric acid, mannitol, N-acetylprocainamide ethobromide, sucrose, and inulin, each was absorbed roughly 2.5 times faster in the mouse than in the rat, and roughly 2.5 times more slowly in the rabbit than in the rat. In contrast, with lipid-soluble drugs, such as antipyrine, salicylic acid, barbital, amitrole and procainamide, each was absorbed at about the same rate in all three species. The results suggest that the porosity of the pulmonary membrane is greatest in the mouse, lower in the rat, and lowest in the rabbit. The observed interspecies relationships in absorption rates suggest that it may be possible to predict the rate of absorption of a given drug in one species from data obtained for the same drug in another species.

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.

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 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.

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.

Enhancement of pulmonary drug absorption in the rat by bromphenol blue and related dyes.

1. Pulmonary absorption studies in the rat showed that intratracheally administered 5-10 mM bromphenol blue, bromcresol green and bromthymol blue markedly increased the absorption rate of 0.1 mM phenol red. 2. Similarly, 1-10 mM bromphenol blue increased the absorption rate of 0.1 mP p-,minohippuric acid, tetraethylammonium and mannitol by 2- to 18-fold in a concentration-dependnet manner. 3. Mannitol absorption was enhanced more by bromthymol blue, sulphobromophthalein, bromcresol purple, thymol blue and bromcresol green than by bromphenol blue or m-cresol purple. Chlorphenol red and phenol red had no effect on mannitol absorption. 4. The results indicated that certain sulphonic acid dyes increase the permeability of the respiratory tract epithelium, perhaps by increasing its porosity.

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.