Evaluating the intestinal and oral absorption of the prodrug valacyclovir in wildtype and huPepT1 transgenic mice

Epling, Daniel; Hu, Yongjun; Smith, David Eugene

doi:10.1016/j.bcp.2018.06.010

Cited by 14 publications

(8 citation statements)

References 29 publications

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“…S3 A ). Although higher than equivalent IC 50 values obtained for natural peptides, which were 72.2 μM for dialanine (AlaAla) and 23.7 μM for trialanine (AlalAlaAla), similar K M values have been reported for valacyclovir uptake in mouse and human PepT1 (23, 24). We were further able to measure both valacyclovir and 5-aminolevulinic acid transport directly using a pyranine-based transport assay that measures proton movement (21) ( SI Appendix , Fig.…”

Section: Resultssupporting

confidence: 65%

Structural basis for prodrug recognition by the SLC15 family of proton-coupled peptide transporters

Minhas

Newstead

2019

Proc. Natl. Acad. Sci. U.S.A.

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SignificancePoor oral bioavailability is one of the leading causes of compound failure in drug development and a major challenge for the pharmaceutical industry. A successful approach to address this challenge has been the development of prodrugs that target the intestinal peptide transporter, PepT1 (SLC15A1). PepT1 exhibits a remarkably promiscuous binding site and is known to transport many different drug molecules, making it an excellent target for prodrug design and delivery. However, the structural basis for drug recognition remains largely unknown. Here we present the structure of a bacterial homolog of PepT1 bound to both an antiviral prodrug, valacyclovir, and anticancer drug 5-aminolevulinic acid. These structures enable a pharmacophore model to be developed that will aid future prodrug design.

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Section: Resultssupporting

confidence: 65%

Structural basis for prodrug recognition by the SLC15 family of proton-coupled peptide transporters

Minhas

Newstead

2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Following centrifugation of the 100-μL perfusate samples, a 25-µL aliquot was injected into the ultra performance liquid chromatography (UPLC) system, as previously described with minor modification [36]. Specifically, the method employed a UPLC Acquity H-Class System (Waters Corp, Milford, MA) coupled to a Photodiode Array Detector set at 254 nm.…”

Section: Methodsmentioning

confidence: 99%

Effect of biphenyl hydrolase-like (BPHL) gene disruption on the intestinal stability, permeability and absorption of valacyclovir in wildtype and Bphl knockout mice

Epling

Shi

et al. 2018

Biochemical Pharmacology

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Biphenyl hydrolase-like protein (BPHL) is a novel human serine hydrolase that was originally cloned from a breast carcinoma cDNA library and shown to convert valacyclovir to acyclovir and valganciclovir to ganciclovir. However, the exclusivity of this process has not been determined and, indeed, it is possible that a number of esterases/proteases may mediate the hydrolysis of valacyclovir and similar prodrugs. The objectives of the present study were to evaluate the in situ intestinal permeability and stability of valacyclovir in wildtype (WT) and Bphl knockout (KO) mice, as well as the in vivo oral absorption and intravenous disposition of valacyclovir and acyclovir in the two mouse genotypes. We found that Bphl knockout mice had no obvious phenotype and that Bphl ablation did not alter the jejunal permeability of valacyclovir during in situ perfusions (i.e., 0.54 × 10 in WT vs. 0.53 × 10 cm/s in KO). Whereas no meaningful changes occurred between genotypes in the gene expression of proton-coupled oligopeptide transporters (i.e., PepT1, PepT2, PhT1, PhT2), enzymatic upregulation of Cyp3a11, Cyp3a16, Abhd14a and Abhd14b was observed in some tissues of Bphl knockout mice. Most importantly, we found that valacyclovir was rapidly and efficiently hydrolyzed to acyclovir in the absence of BPHL, and that hydrolysis was more extensive after the oral vs. intravenous route of administration (for both genotypes). Taken as a whole, BPHL is not obligatory for the conversion of valacyclovir to acyclovir either presystemically or systemically.

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“…Twenty-four hour urinary and faecal recovery experiments were performed for TCMCB07 as described previously by our laboratory. 22 In brief, mice were fasted the night prior to experimentation for 16-18 h, and then, 100 μL (10 μCi) per 20 g mouse of [ 3 H]inulin was administered into the tail vein by intravenous bolus injection. This was followed immediately by dosing 200 μL (5 μCi) per 20 g mouse of [ 14 C]TCMCB07 (23.3 mg/kg) by oral gavage.…”

Section: Mass Balance Studiesmentioning

confidence: 99%

Characterization of the cellular transport mechanisms for the anti‐cachexia candidate compound TCMCB07

Gruber

Smith

2020

J cachexia sarcopenia muscle

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Background Cachexia is a debilitating, life-threatening condition whose pathology includes reduced food intake accompanied by hypermetabolism, leading to a catabolic state. The hypothalamic melanocortin system is a critical regulator of metabolic rate with effects being mediated through the melanocortin-4 receptor (MC4R). MC4R activation is also critical to the initiation and maintenance of cachexia. A major problem in the design of anti-cachexia drugs has been the need to cross the blood-brain barrier to access the metabolic rate-controlling centres in the hypothalamus. The overwhelming majority of anti-cachexia drugs are only effective when administered intracerebroventricularly. TCMCB07 is a cyclic nonapeptide peptide MC4R antagonist with parenteral anti-cachexia activity in both small and large animal models. This suggests it can cross the blood-brain barrier. The aim of this study was to examine potential transport mechanisms of TCMCB07 furthering its preclinical development for subsequent studies in humans. Methods In vitro studies were performed in transporter-transfected cells to study whether or not TCMCB07 was an inhibitor as well as substrate for OATP1A2, OATP1B1, OATP1B3, OATP2B1, OCT2, OAT1, OAT3, MATE1, MATE2-K, P-gp (MDR1), and BCRP. In vivo mass balance studies were also performed in mice to evaluate the absorption and disposition of TCMCB07 after oral and intravenous bolus administrations. Results TCMCB07 inhibited the uptake of prototypical substrates in cells transfected with OATP1A2 (IC 50 24.0 μM), OATP1B1 (IC 50 6.8 μM), OATP1B3 (IC 50 307 μM), OATP2B1 (IC 50 524 μM), OCT2 (IC 50 1,169 μM), MATE1 (IC 50 8.7 μM), and MATE2-K (IC 50 20.7 μM) but not in cells transfected with OAT1 and OAT3. TCMCB07 did not affect the P-gp (MDR1)-mediated and BCRP-mediated permeability of prototypical substrates in transfected cells. Importantly, direct evidence was shown for the uptake of TCMCB07 in OATP1A2-transfected cells (i.e. V max 236 pmol/mg, K m 58.4 μM, and K d 0.39 μL/mg), demonstrating that the nonapeptide was a substrate for this transporter. Mass balance studies demonstrated that 24.2% of TCMCB07 was absorbed orally in vivo (P = 0.0033) and excreted primarily in the bile after both oral and intravenous administrations. Conclusions OATP1A2 is the transporter responsible for the oral absorption of TCMCB07 in the intestine and for its pharmacologic response in the brain.

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Evaluating the intestinal and oral absorption of the prodrug valacyclovir in wildtype and huPepT1 transgenic mice

Cited by 14 publications

References 29 publications

Structural basis for prodrug recognition by the SLC15 family of proton-coupled peptide transporters

Structural basis for prodrug recognition by the SLC15 family of proton-coupled peptide transporters

Effect of biphenyl hydrolase-like (BPHL) gene disruption on the intestinal stability, permeability and absorption of valacyclovir in wildtype and Bphl knockout mice

Characterization of the cellular transport mechanisms for the anti‐cachexia candidate compound TCMCB07

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