Biodegradation characteristics of acyclovir 2′-esters by respiratory carboxylesterases: Implications in prodrug design for intranasal and pulmonary drug delivery

https://doi.org/10.1016/0378-5173(94)90428-6Get rights and content

Abstract

Eight aliphatic and one aromatic 2′-ester prodrugs of 9-(2-hydroxyethoxymethyl)guanine (acyclovir) were incubated with rat nasal mucosal homogenate in vitro to characterize their degradation kinetics by carboxylesterase. Lineweaver-Burk plots revealed that prodrugs with longer linear carboxylic side chains possess higher Vmax and smaller Km values than esters with shorter side chains, probably as a result of improved lipophilicity. Under subsaturating conditions, the rate and extent of prodrug degradation assume a direct relationship with acyl side chain length. Lengthening of linear carboxylic chains from three to eight carbons resulted in a more than 600-fold increase in first-order degradation rate constants. Esters with branched acyl chains are more resistant to nasal carboxylesterase-mediated cleavage. Acyclovir benzoate, on the other hand, did not afford specific protective effect against nasal carboxylesterase, although such an effect was found in plasma. Comparison of the second-order rate constants for binding and catalysis (Vmax/Kmax) indicated that the catalytic affinity of nasal carboxylesterase differs significantly from that of ester hydrolase in plasma. Comparison of hexanoate degradation kinetics in tracheal, pulmonary parenchymal, and nasal homogenates suggested that nasal mucosa possesses the highest carboxylesterase activity in the respiratory tract. The uniquely rich presence of this enzyme in the nasal cavity forms a remarkable enzymatic barrier to prodrug design for systemic delivery.

References (29)

  • M.S. Bogdanffy et al.

    Metabolism of dibasic esters by rat nasal mucosal carboxylesterase

    Drug Metab. Dispos.

    (1991)
  • Y.W. Chien et al.

    Nasal Systemic Drug Delivery

    (1989)
  • M.J.M. Deurloo et al.

    Absorption enhancement of intransally administered insulin by sodium taurodihydrofusidate (STDHF) in rabbits and rats

    Pharm. Res.

    (1989)
  • D. Duchêne et al.

    Nasal administration: A tool for tomorrow's systemic administration of drugs

    Drug Del. Ind. Pharm.

    (1993)
  • Cited by (11)

    • Novel Insights to Enhance Therapeutics With Acyclovir in the Management of Herpes Simplex Encephalitis

      2021, Journal of Pharmaceutical Sciences
      Citation Excerpt :

      β-cyclodextrin complexes with acyclovir also increased significantly the drug solubility in water (7.6-fold), pH 1.2 (9.5-fold), and pH 7.4 (6-fold), which is an interesting finding when a high-dose of acyclovir is needed to treat infections. Administration of acyclovir prodrugs represents an approach to improve drug absorption and bioavailability.97–101 Besides improving the permeability parameters, prodrugs can have a high affinity for influx transporters, increasing the drug absorption rate.

    • Protein and Peptide Delivery through Respiratory Pathway

      2011, Challenges in Delivery of Therapeutic Genomics and Proteomics
    • Prodrugs for nasal drug delivery

      1998, Advanced Drug Delivery Reviews
    View all citing articles on Scopus
    View full text