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Pharmacokinetics of amino acid ester prodrugs of acyclovir after oral administration: interaction with the transporters on Caco-2 cells.
Int J Pharm. 2008 Oct 01; 362(1-2):93-101.IJ

Abstract

In vivo systemic absorption of the amino acid prodrugs of acyclovir (ACV) after oral administration was evaluated in rats. Stability of the prodrugs, L-alanine-ACV (AACV), L-serine-ACV (SACV), L-isoleucine-ACV (IACV), gamma-glutamate-ACV (EACV) and L-valine-ACV (VACV) was evaluated in various tissues. Interaction of these prodrugs with the transporters on Caco-2 cells was studied. In vivo systemic bioavailability of these prodrugs upon oral administration was evaluated in jugular vein cannulated rats. The amino acid ester prodrugs showed affinity towards various amino acid transporters as well as the peptide transporter on the Caco-2 cells. In terms of stability, EACV was most enzymatically stable compared to other prodrugs especially in liver homogenate. In oral absorption studies, ACV and AACV showed high terminal elimination rate constants (lambda(z)). SACV and VACV exhibited approximately five-fold increase in area under the curve (AUC) values relative to ACV (p<0.05). C(max(T)) (maximum concentration) of SACV was observed to be 39+/-22 microM in plasma which is 2 times better than VACV and 15 times better than ACV. C(last(T)) (concentration at the last time point) of SACV was observed to be 0.18+/-0.06 microM in plasma which is two times better than VACV and three times better than ACV. Amino acid ester prodrugs of ACV were absorbed at varying amounts (C(max)) and eliminated at varying rates (lambda(z)) thereby leading to varying extents (AUC). The amino acid ester prodrug SACV owing to its enhanced stability, higher AUC and better concentration at last time point seems to be a promising candidate for the oral treatment of herpes infections.

Authors+Show Affiliations

Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhill Road, Kansas City, MO 64110-2499, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

18638532

Citation

Katragadda, Suresh, et al. "Pharmacokinetics of Amino Acid Ester Prodrugs of Acyclovir After Oral Administration: Interaction With the Transporters On Caco-2 Cells." International Journal of Pharmaceutics, vol. 362, no. 1-2, 2008, pp. 93-101.
Katragadda S, Jain R, Kwatra D, et al. Pharmacokinetics of amino acid ester prodrugs of acyclovir after oral administration: interaction with the transporters on Caco-2 cells. Int J Pharm. 2008;362(1-2):93-101.
Katragadda, S., Jain, R., Kwatra, D., Hariharan, S., & Mitra, A. K. (2008). Pharmacokinetics of amino acid ester prodrugs of acyclovir after oral administration: interaction with the transporters on Caco-2 cells. International Journal of Pharmaceutics, 362(1-2), 93-101. https://doi.org/10.1016/j.ijpharm.2008.06.018
Katragadda S, et al. Pharmacokinetics of Amino Acid Ester Prodrugs of Acyclovir After Oral Administration: Interaction With the Transporters On Caco-2 Cells. Int J Pharm. 2008 Oct 1;362(1-2):93-101. PubMed PMID: 18638532.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetics of amino acid ester prodrugs of acyclovir after oral administration: interaction with the transporters on Caco-2 cells. AU - Katragadda,Suresh, AU - Jain,Ritesh, AU - Kwatra,Deep, AU - Hariharan,Sudharshan, AU - Mitra,Ashim K, Y1 - 2008/06/27/ PY - 2008/04/09/received PY - 2008/06/17/revised PY - 2008/06/18/accepted PY - 2008/7/22/pubmed PY - 2009/4/21/medline PY - 2008/7/22/entrez SP - 93 EP - 101 JF - International journal of pharmaceutics JO - Int J Pharm VL - 362 IS - 1-2 N2 - In vivo systemic absorption of the amino acid prodrugs of acyclovir (ACV) after oral administration was evaluated in rats. Stability of the prodrugs, L-alanine-ACV (AACV), L-serine-ACV (SACV), L-isoleucine-ACV (IACV), gamma-glutamate-ACV (EACV) and L-valine-ACV (VACV) was evaluated in various tissues. Interaction of these prodrugs with the transporters on Caco-2 cells was studied. In vivo systemic bioavailability of these prodrugs upon oral administration was evaluated in jugular vein cannulated rats. The amino acid ester prodrugs showed affinity towards various amino acid transporters as well as the peptide transporter on the Caco-2 cells. In terms of stability, EACV was most enzymatically stable compared to other prodrugs especially in liver homogenate. In oral absorption studies, ACV and AACV showed high terminal elimination rate constants (lambda(z)). SACV and VACV exhibited approximately five-fold increase in area under the curve (AUC) values relative to ACV (p<0.05). C(max(T)) (maximum concentration) of SACV was observed to be 39+/-22 microM in plasma which is 2 times better than VACV and 15 times better than ACV. C(last(T)) (concentration at the last time point) of SACV was observed to be 0.18+/-0.06 microM in plasma which is two times better than VACV and three times better than ACV. Amino acid ester prodrugs of ACV were absorbed at varying amounts (C(max)) and eliminated at varying rates (lambda(z)) thereby leading to varying extents (AUC). The amino acid ester prodrug SACV owing to its enhanced stability, higher AUC and better concentration at last time point seems to be a promising candidate for the oral treatment of herpes infections. SN - 1873-3476 UR - https://www.unboundmedicine.com/medline/citation/18638532/Pharmacokinetics_of_amino_acid_ester_prodrugs_of_acyclovir_after_oral_administration:_interaction_with_the_transporters_on_Caco_2_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-5173(08)00454-7 DB - PRIME DP - Unbound Medicine ER -