Stability of valacyclovir: Implications for its oral bioavailability

Granero, Gladys E.; Amidon, Gordon L.

doi:10.1016/j.ijpharm.2006.01.050

Cited by 62 publications

(49 citation statements)

References 15 publications

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“…Moreover, after colonic administration of 20 mg/kg valacyclovir to rats, there was no indication of prodrug absorption as evidenced by the lack of detectable plasma levels of acyclovir (Kagan and Hoffman, 2008). Finally, in light of the extensive luminal degradation of valacyclovir (Granero and Amidon, 2006) and the high fraction of acyclovir excreted in feces after oral dosing (de Miranda et al, 1981), it is unlikely that the colonic transporter ATB 0,+ would make a meaningful contribution to the intestinal absorption of valacyclovir.…”

Section: Discussionmentioning

confidence: 98%

Significance of Peptide Transporter 1 in the Intestinal Permeability of Valacyclovir in Wild-Type and PepT1 Knockout Mice

Yang

Smith

2012

Drug Metab Dispos

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The purpose of this study was to quantitatively determine the contribution of PepT1 [peptide transporter 1 (SLC15A1)] to the intestinal permeability of valacyclovir, an ester prodrug of the antiviral drug acyclovir. In situ single-pass intestinal perfusions were employed (pH 6.5 3 90 minutes) to assess the effective permeability (P eff ) of 100 mM [ 3 H]valacyclovir in wild-type and PepT1 knockout mice. Acyclovir pharmacokinetics was also evaluated after oral administration of 25 nmol/g valacyclovir. In wild-type mice, jejunal uptake of valacyclovir was best described by both saturable (K m = 10.2 mM) and nonsaturable components where the saturable pathway accounted for 82% of total transport. Valacyclovir P eff was 2.4 3 10 24 cm/s in duodenum, 1.7 3 10 24 cm/s in jejunum, 2.1 3 10 24 cm/s in ileum, and 0.27 3 10 24 cm/s in colon. In Pept1 knockout mice, P eff values were about 10% of that in wild-type animals for these small intestinal segments. Valacyclovir P eff was similar in the colon of both genotypes. There were no differences in valacyclovir P eff between any of the intestinal segments of PepT1 knockout mice. Valacyclovir P eff was significantly reduced by the dipeptide glycylsarcosine and the aminocephalosporin cefadroxil, but not by the amino acids L-valine or L-histidine, the organic acid p-aminohippurate, or the organic base tetraethylammonium (all at 25 mM). PepT1 ablation resulted in 3-to 5-fold reductions in the in vivo rate and extent of valacyclovir absorption. Our findings conclusively demonstrate, using in situ and in vivo validations in genetically modified mice, that PepT1 has a major influence in improving the oral absorption of valacyclovir.

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Section: Discussionmentioning

confidence: 98%

Significance of Peptide Transporter 1 in the Intestinal Permeability of Valacyclovir in Wild-Type and PepT1 Knockout Mice

Yang

Smith

2012

Drug Metab Dispos

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“…After absorption, it is bioactivated by valacyclovir hydrolase (Burnette et al, 1995). The bioavailability of this prodrug is more than 50%, which is 20 to 35% better than the bioavailability of acyclovir (Granero and Amidon, 2006). Valacyclovir is actually a preprodrug or double prodrug, because after the hydrolysis of the valine promoiety, acyclovir, like all nucleosides, requires phosphorylation before it forms the active nucleotide triphosphate.…”

Section: B Enhancing Permeability and Absorptionmentioning

confidence: 99%

Prodrugs—from Serendipity to Rational Design

2011

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“…(Granero et al, 2006) Such luminal hydrolysis will minimize the amount of intact prodrug available to the transporter on the intestinal epithelium. Enzymatically stable prodrugs are needed in order to increase the both the oral as well as the ocular bioavailability of acyclovir after oral administration.…”

Section: Introductionmentioning

confidence: 99%