Abstract
Purpose. To evaluate the intratracheal route of administration as an alternative to oral administration for 2′,3′-dideoxyinosine (ddI).
Methods. A ddI dose (40 mg/kg/300 µl or 6.5 mg/kg/50 µl) was instilled into the trachea in female Fisher rats and an intravenous tracer dose (9 µg/kg) of 3H-ddI was administered concomitantly to determine the drug clearance. Plasma concentrations were analyzed for the rate and extent of absorption.
Results. ddI was rapidly absorbed from the lungs, with a bioavailability of 63% at 40 mg/kg and 101% at 6.5 mg/kg. By comparison, our previous data showed an oral bioavailability of about 15% (Pharm Res., 9:822, 1992). The distribution of a dye solution instilled intratracheally showed that a fraction of the 300 µL dose spilled over to the gastrointestinal tract, where the entire 50 µL dose was retained in the lungs. The different distribution of the two doses/volumes likely contributed to the different bioavailability, with a fraction of the higher dose/volume degraded in the gastrointestinal tract after the spillover. Absorption of ddI from the airspace of the lung was biexponential, suggesting two absorption processes.
Conclusions. These data indicate significantly higher and less variable bioavailability of ddI by the intratracheal route of delivery compared to the oral route. Furthermore, the complete bioavailability at the lower dose/volume indicates no significant pulmonary first pass elimination for ddI.
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REFERENCES
H. Mitsuya and S. Broder. Strategies for anti-viral therapy in AIDS. Nature 325:773–778 (1987).
E. Declerq. Design of anti-AIDS drugs, Elsevier, NY, (1990).
S.L. Bramer, J. L.-S. Au, and M.G. Wientjes. Gastrointestinal and hepatic first pass elimination of 2′,3′-dideoxyinosine in rats. J. Pharmacol. Exp. Ther. 256:731–738 (1994).
V.E. Marquez, C.H. Tseng, J.A. Kelly, H. Mitsuya, S. Border, J.S. Roth and J.S. Driscoll. 2′,3′-dideoxy-2′-fluoro-ara-A. An acid stable purine nucleoside active against human immunodeficiency virus (HIV). Biochem. Pharmacol. 36:2719–2722 (1987).
N.R. Hartman, R. Yarchoan, J.M. Pluda, and R.V. Thomas, K.S. Marcyzk, S. Broder, and D.G. Johns. Pharmacokinetics of 2′,3′-dideoxyadenosine and 2′,3′-dideoxyinosine in patients with severe human immunodeficiency virus infection. Clin. Pharmacol. Ther. 47:647–654 (1990).
C.A. Knupp, W.C. Shyu, R. Dolin, F.T. Valentine, C. McLaren, R.R. Martin, K.A. Pitman, and R.H. Barbhaiya. Pharmacokinetics of didanosine in patients with acquired immunodeficiency syndrome and acquired immunodeficiency syndrome related complex. Clin. Pharmacol. Ther. 49:523–535 (1991).
S.L. Bramer, M.G. Wientjes, and J. L.-S. Au. Absorption of 2′,3′-dideoxyinosine from lower gastrointestinal tract in rats and kinetic evidence of different absorption rates in colon and rectum. Pharm. Res. 10:763–770 (1993).
E. Mukherji, N.J. Millenbaugh, and J. L.-S. Au. Percutaneous absorption of 2′,3′-dideoxyinosine in rats. Pharm. Res. 11:809–815 (1994).
E. Gupta, M.G. Wientjes, and J. L.-S. Au. Penetration kinetics of 2′,3′-dideoxyinosine in dermis is described by the distributed model. Pharm. Res. 12:106–120 (1995).
P.K. Gupta and A.J. Hickey. Contemporary approaches in aerosolized drug delivery to the lung. J. Controlled Release 17:129–148 (1991).
M.G. Levitzky. Pulmonary Physiology, McGraw Hill, NY, 2nd ed., 1986.
L.S. Shanker and M.J. Less. Lung pH and pulmonary absorption of non volatile drugs in the rat. Drug Metab. Disp., 5:174–178 (1977).
S. Kobayashi, S. Kondo, and K. Juni. Study on pulmonary delivery of salmon calcitonin in rats: Effect of protease inhibitors and absorption enhancers. Pharm. Res. 11:1239–1243 (1994).
J.D. Catravas, J.S. Lazo, K.J. Dobuler, L.R. Mills, and C.N. Gillis. Pulmonary endothelial dysfunction in the presence or absence of interstitial injury induced by intratracheally injected bleomycin in rabbits. Am Rev. Respir. Dis. 128:740–746 (1983).
L.S. Shanker. Drug absorption from the lung. Biochem. Pharmacol. 27:381–385 (1978).
M.G. Wientjes, E. Mukherji, and J. L.-S. Au. Nonlinear disposition of intravenous 2′,3′-dideoxyinosine in rats. Pharm. Res. 9:1070–1075 (1993).
B. Sun, E. Herting, T. Curstedt, and B. Robertson. Exogenous surfactant improves lung compliance and oxygenation in adult rats with meconium aspiration. J. Appl. Physiol. 77:1961–1971 (1994).
M.G. Wientjes and J. L.-S. Au. High performance liquid chromatographic analysis of 2′,3′-dideoxyinosine in biological samples. J. Chromatogr. 563:400–406 (1991).
M. Rowland and T.N. Tozer. Clinical Pharmacokinetics, Concepts and Applications, Lea and Febiger, Philadelphia, 1980.
L.Z. Benet and R.L. Galeazzi. Noncompartmental determination of the steady state volume of distribution. J. Pharm. Sci. 68:1071–1074 (1979).
R.C. Shumaker, H. Boxenbaum and G.A. Thompson. ABSPLOTS: A Lotus 123 spreadsheet for calculating and plotting drug absorption rates. Pharm. Res. 5:247–248 (1988).
M. Gilbaldi, and D. Perrier. Pharmacokinetics, 2nd edition. Marcel Dekker, Inc., New York, 1982.
SCI Software Statistical Consultants, Inc., PCNONLIN User's Guide, Version 3.0. SCI Software Statistical Consultants, Inc., Lexington, KY, 1989, pp 3-1–3-7.
B.P. Imbimbo, P. Martinelli, M. Rocchettit, G. Ferrari, G. Bassotti, and E. Imbimbo. Efficiency of different criteria for selecting pharmacokinetic multiexponential equations. Biopharm. Drug Disp. 12:139–147 (1991).
A.W. Wanner and M.A. Sackner. Pulmonary diseases: mechanisms of altered structure and function. Little, Brown, Boston, 1983.
M. Aihara, R.P. Sharma and J.L. Shape. Short term disposition of soluble vs. insoluble forms of cadmium in rat lung after intratracheal administration: An autoradiographic assessment. Toxicology, 36:109–118 (1985).
M.G. Wientjes and J. L.-S. Au. Pharmacokinetics of oral 2′,3′-dideoxyinosine in rats. Pharm. Res. 9:822–825 (1992).
K.-J. Kim and E.D. Crandall. Specialized alveolar epithelial transport processes. In Fluid and Solute Transport in the Airspaces of the Lungs, ed. R. M. Effros and H. K. Chang, Marcel Dekker, Inc., NY, 1994.
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Gao, X., Wientjes, M.G. & Au, J.LS. Extensive Absorption of 2′,3′-Dideoxyinosine by Intratracheal Administration in Rats. Pharm Res 12, 1901–1906 (1995). https://doi.org/10.1023/A:1016283604540
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DOI: https://doi.org/10.1023/A:1016283604540