Abstract
A series of 2′-(O-acyl) derivatives of 9-(2-hydoxyethoxymethyl)guanine (acyclovir) was synthesized by acid anhydride esterification. Aqueous solubilities in isotonic phosphate buffer (pH 7.4), partition coefficients in 1-octanol/phosphate buffer, and hydrolysis kinetics in rat plasma were determined. The ester prodrugs showed consistent increases in lipophilicity with corresponding decreases in aqueous solubility as a function of side-chain length. The bioconversion kinetics of the prodrugs appear to depend on both the apolar and the steric nature of the acyl substituents. When perfused through the rat nasal cavity using the in situ perfusion technique, acyclovir showed no measurable loss from the perfusate. Nasal uptake of acyclovir prodrugs, on the other hand, were moderately improved. Furthermore, the extent of nasal absorption appears to depend on the lipophilicity of the prodrugs in the descending order hexanoate > valerate > pivalate > butyrate. Simultaneous prodrug cleavage by nasal carboxylesterase was also noted in the case of hexanoate.
Similar content being viewed by others
REFERENCES
Y. W. Chien, K. S. E. Su, and S. F. Chang. Nasal Systemic Drug Delivery, Marcel Dekker, New York, 1989.
P. Tengamnuay and A. K. Mitra. Bile salt-fatty acid mixed micelles as nasal absorption promoters of peptides. II. In vivo nasal absorption of insulin in rats and effects of mixed micelles on the morphological integrity of the nasal mucosa. Pharm. Res. 7:370–375 (1990).
S. Hirai, T. Yashiki, and H. Mima. Effects of surfactants on the absorption of insulin in rats. Int. J. Pharm. 9:165–172 (1981).
J. P. Longenecker A. C. Moses, J. S. Flier, R. D. Silver, M. C. Carey, and E. J. Dubovi. Effects of sodium taurodihydrofusidate on nasal absorption of insulin in sheep. J. Pharm. Sci. 76:351–355 (1987).
M. J. M. Deurloo, W. A. J. J. Hermens, S. G. Romeyn, J. C. Verhoef, and F. W. H. M. Merkus. Absorption enhancement of intranasally administered insulin by sodium taurodihydrofusidate (STDHF) in rabbits and rats. Pharm. Res. 6:853–856 (1989).
P. A. Baldwin, C. K. Klingbell, C. J. Grimm, and J. P. Longenecker. The effect of sodium tauro-24, 25-dihydrofusidate on the nasal absorption of human growth hormone in three animal models. Pharm. Res. 7:547–552 (1990).
M. Mishima, Y. Wakita, and M. Nakano. Studies on the promoting effects of medium chain fatty acid salts on the nasal absorption of insulin in rats. J. Pharmacobiodyn. 10:624–631 (1987).
S. Hirai, T. Yashiki, and H. Mima. Mechanisms for the enhancement of the nasal absorption of insulin by surfactants. Int. J. Pharm. 9:173–184 (1981).
M. D. Donovan, G. L. Flynn, and G. L. Amidon. The molecular weight dependence of nasal absorption enhancers. Pharm. Res. 7:808–815 (1990).
Z. Shao, R. Krishnamoorthy, and A. K. Mitra. Cyclodextrins as nasal absorption promoters of insulin: Mechanistic evaluations. Pharm. Res. 9:1157–1163 (1992).
Z. Shao and A. K. Mitra. Nasal membrane and intracellular protein and enzyme release by bile salts and bile salt-fatty acid mixed micelles: Correlation with facilitated drug transport. Pharm. Res. 9:1184–1189 (1992).
T. Kissel, J. Drewe, S. Bantle, A. Rummelt, and C. Beglinger. Tolerability and absorption enhancement of intranasally administered octreotide by sodium taurodihydrofusidate in healthy subjects. Pharm. Res. 9:52–57 (1992).
C. H. Huang, R. Kimura, R. B. Nassar, and A. Hussain. Mechanism of nasal absorption of drugs. I. Physicochemical parameters influencing the rate of in situ nasal absorption of drugs in rats. J. Pharm. Sci. 74:608–611 (1985).
C. H. Huang, R. Kimura, R. Bawarshi-Nassar, and A. Hussain. Mechanism of nasal absorption of drugs. II. Absorption of L-tyrosine and the effect of structural modification on its absorption. J. Pharm. Sci. 74:1298–1301 (1985).
D. C. Corbo, Y. C. Huang, and Y. W. Chien. Nasal delivery of progestational steroids in ovariectomized rabbits. II. Effect of penetrant hydrophilicity. Int. J. Pharm. 50:253–260 (1989).
D. C. Corbo, J.-C. Liu, and Y. W. Chien. Drug absorption through mucosal membranes: Effect of mucosal route and penetrant hydrophilicity. Pharm. Res. 6:848–852 (1989).
M. M. Narurkar and A. K. Mitra. Synthesis, physicochemical properties, and cytotoxicity of a series of 5′-ester prodrugs of 5-iodo-2′deoxyuridine. Pharm. Res. 5:734–737 (1988).
M. K. Ghosh and A. K. Mitra. Effects of 5′-ester modification on the physicochemical properties and plasma protein binding of 5-iodo-2′-deoxyuridine. Pharm. Res. 6:771–775 (1991).
A. G. Gilman, L. S. Goodman, T. W. Rall, and F. Murad (eds.). The Pharmacological Basis of Therapeutics, Macmillan, New York, 1986, pp. 1229–1231.
L. M. Beauchamp, G. F. Orr, P. de Miranda, T. Burnette, and T. A. Krenitsky. Amino acid ester prodrugs of acyclovir. Antiviral Chem. Chemother. 3:157–164 (1992).
G.-B. Park, Z. Shao, and A. K. Mitra. Acyclovir permeation enhancement across intestinal and nasal mucosae by bile salt-acylcarnitine mixed micelles. Pharm. Res. 9:1262–1267 (1992).
M. R. Harnden, P. G. Wyatt, M. R. Boyd, and D. Sutton. Synthesis and antiviral activity of 9-alkoxypurines. 1. 9-(3-Hydroxypropoxy)-and 9-[3-hydroxy-2-(hydroxymethyl)propoxy] purines. J. Med. Chem. 33:187–196 (1990).
S. Hirai, T. Yashiki, T. Matsuzawa, and H. Mima. Absorption of drugs from the nasal mucosa of rat. Int. J. Pharm. 7:317–325 (1981).
G. Land and A. Bye. Simple high-performance liquid chromatographic method for the analysis of 9-(2-hydroxyethoxymethyl) guanine [acyclovir] in human plasma and urine. J. Chromatogr. 224:51–58 (1981).
C. Hansch and A. Leo. Substituent Constants for Correlation Analysis in Chemistry and Biology, John Wiley and Sons, New York, 1979.
B. H. Hofstee. Specificity of esterases. II. Behavior of pancreatic esterases I and II toward a homologous series of n-fatty acid esters. J. Biol. Chem. 199:365–371 (1952).
M. K. Ghosh and A. K. Mitra. Enhanced delivery of 5-iodo-2′-deoxyuridine to the brain parenchyma. Pharm. Res. 9:1173–1176 (1992).
M. A. Sarkar. Drug metabolism in the nasal mucosa. Pharm. Res. 9:1–9 (1992).
W. T. Stott and M. J. McKenna. Hydrolysis of several glycol ether acetates and acrylate esters by nasal mucosal carboxylesterase in vitro. Fund. Appl. Toxicol. 5:399–404 (1985).
Z. Shao and A. K. Mitra. Bile salt-fatty acid mixed micelles as nasal absorption promoters III. Effects on nasal transport and enzymatic degradation of acyclovir prodrugs. Pharm. Res. 11:243–250 (1994).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Shao, Z., Park, GB., Krishnamoorthy, R. et al. The Physicochemical Properties, Plasma Enzymatic Hydrolysis, and Nasal Absorption of Acyclovir and Its 2′-Ester Prodrugs. Pharm Res 11, 237–242 (1994). https://doi.org/10.1023/A:1018903407592
Issue Date:
DOI: https://doi.org/10.1023/A:1018903407592