Abstract
It has been reported that conjugating acyclovir, a potent antiviral with low oral bioavailability, to l-valine increases its urinary excretion in rats. However, it was also reported that this increase is not found for the d-valine ester, suggesting that a carrier-mediated mechanism is involved in its intestinal absorption. Therefore, mechanisms involved in the transepithelial transport of l-valine-acyclovir were investigated using the intestinal cell line, Caco-2, as a model system for the intestinal epithelium. Only the mucosal-to-serosal transport of acyclovir was increased by conjugation with l-valine (∼7-fold), suggesting the involvement of a carrier-mediated mechanism. This conclusion was supported by the finding that this increase was saturable. The mucosal-to-serosal transport ofl-valine-acyclovir could be inhibited byl-glycylsarcosine, but not by l-valine, suggesting the involvement of the dipeptide carrier. Also it was found that l-valine-acyclovir inhibits the uptake of cephalexin, a substrate for the oligopeptide transporter. Stability of the esters in either the mucosal or serosal bathing solution is more than 90% after completion of the transport study. However, after transport, the receiver solution contained approximately 90% of acyclovir. Based on these findings it was concluded that absorption of thel-valine ester of acyclovir occurs as a result of uptake by the oligopeptide transporter at the apical cell membrane followed by intracellular hydrolysis of the ester and efflux of acyclovir.
Footnotes
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Send reprint requests to: Dr. Chao-Pin Lee, Department of Drug Delivery UP1230, SmithKline Beecham Pharmaceuticals, 1250 South Collegeville Road, P.O. Box 5089, Collegeville, PA 19426-0989.
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↵1 Current address: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
- Abbreviations:
- GI
- gastrointestinal
- Gly-Sar
- L-glycyl-sarcosine
- L-val-acv
- L-val-acyclovir
- m
- mucosal
- S
- serosal
- cbz
- benzyl carbamate
- [H]NMR
- proton nuclear magnetic resonance
- DMEM
- Dulbecco’s Modified Eagle medium
- NEAA
- non-essential amino acid solution
- Received January 28, 1998.
- Accepted May 12, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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