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Characterization of the Intestinal Permeability and Oral Absorption of Valacyclovir in Wildtype and huPepT1 Transgenic Mice
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Characterization of the Intestinal Permeability and Oral Absorption of Valacyclovir in Wildtype and huPepT1 Transgenic Mice. |
| 개인저자 | Epling, Daniel. |
| 단체저자명 | University of Michigan. Pharmaceutical Sciences. |
| 발행사항 | [S.l.]: University of Michigan., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 127 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-05B. Dissertation Abstract International |
| ISBN | 9781687934376 |
| 학위논문주기 | Thesis (Ph.D.)--University of Michigan, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-05, Section: B.
Advisor: Smith, David Eric. |
| 이용제한사항 | This item must not be sold to any third party vendors.This item must not be added to any third party search indexes. |
| 요약 | PepT1 (SLC15A1) is a transporter apically expressed along the epithelial cells of the gastrointestinal tract and is responsible for the absorption of di/tripeptides, ACE inhibitors, 棺-lactam antibiotics and numerous prodrugs. Unfortunately, PepT1-mediated substrates that have been extensively studied were shown to exhibit species-dependent absorption and pharmacokinetics. Accordingly, in situ intestinal perfusion studies were conducted and valacyclovir uptake was shown to have a 30-fold lower Km and 100-fold lower Vmax in huPepT1 compared to wildtype mice. Moreover, inhibition studies demonstrated that the huPepT1 transporter alone was responsible for valacyclovir uptake, and segment-dependent studies reported significant reductions in permeability along the length of small intestine in huPepT1 mice. Subsequent oral administration studies revealed that the in vivo rate and extent of valacyclovir absorption were lower in huPepT1 mice, as indicated by 3-fold lower Cmax and 3-fold higher Tmax values, and an AUC0-180 that was 80% of that observed in wildtype mice. However, no significant changes in drug disposition were observed between genotypes after intravenous bolus administration of acyclovir. Lastly, mass balance studies established that the bioavailability of acyclovir, after oral dosing of valacyclovir, was 77.5% in wildtype mice and 52.8% in huPepT1 mice, which corroborated values of 51.3% in clinical studies. Thus, it appears the huPepT1 transgenic mice may be a better model to study prodrug absorption and disposition in humans than wildtype mice.Additional studies were conducted to determine the impact of nifedipine, a calcium channel blocker, on the PepT1-mediated uptake of valacyclovir in wildtype mice. It has been previously demonstrated in clinical studies, rat intestinal perfusion studies, and Caco-2 uptake studies that nifedipine enhanced the absorption of 棺-lactam antibiotics. However, co-perfusing nifedipine with valacyclovir revealed that the intestinal permeability of valacyclovir was not significantly altered in the presence of this calcium channel blocker, although a 25-30% reduction was observed. While the results obtained in these studies are difficult to reconcile, there may be a species-dependent mechanism in mice that negates the permeability enhancement of PepT1 substrates. |
| 일반주제명 | Pharmaceutical sciences. Cellular biology. |
| 언어 | 영어 |
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