Improved Intestinal Transport of PD 158473, an N-methyl-d-Aspartate (NMDA) Antagonist, by Involvement of Multiple Transporters

Oh, Doo Man; Han, Hyo Kyung; Williamson, Rufus M.; Bigge, Christopher F.; Amidon, Gordon L.; Stewart, Barbra H.; Surendran, Narayanan

doi:10.1002/jps.10241

Cited by 6 publications

(1 citation statement)

References 21 publications

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“…Human PEPT1 transporter protein, which is expressed predominantly but not exclusively, in the small intestine, is a well-characterized influx transporter with many peptidelike substrates such as angiotensin-converting enzyme inhibitors, β-lactam antibiotics (both cephalosporins and penicillins), valacyclovir, and renin inhibitors (Oh et al, 2002;Katsura and Inui, 2003;Friend, 2004). The gene sequences of PEPT1 transporter appear to be highly conserved in rats, dogs, and humans, with the rat and dog gene sequences being 82 and 85%, respectively, identical to the sequence in humans (Perkins et al, 2007).…”

Section: Mechanism Of Oral Absorptionmentioning

confidence: 99%

Anatomical and Physiological Factors Affecting Oral Drug Bioavailability in Rats, Dogs, and Humans

El‐Kattan

Hurst

Brodfuehrer

et al. 2011

Oral Bioavailability

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Section: Mechanism Of Oral Absorptionmentioning

confidence: 99%

Anatomical and Physiological Factors Affecting Oral Drug Bioavailability in Rats, Dogs, and Humans

El‐Kattan

Hurst

Brodfuehrer

et al. 2011

Oral Bioavailability

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Peroral Toxicity

Brock¹

2009

General, Applied and Systems Toxicology

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Numerous factors will affect the passage of drugs and chemicals through the gastrointestinal tract and into systemic circulation. These factors involve anatomical and physiological features, species differences and biochemical features, including intestinal metabolism and effects on transporters. With regard to assessing potential risk of humans to chemicals, these features will need to be considered as there will be differences between experimental animals and humans. The cellular environment of the gastrointestinal tract and the molecular mechanisms of absorption will have a major influence on the bioavailability of drugs and chemicals. The pH of the local cell environment will affect the ionization status of the compound, whereas a drug may inhibit cellular transport of other substances, for example, nutrients, potentially having an affect on the nutritional status of the animal. Moreover, there has been demonstrated evidence that some xenobiotics will affect the metabolic status of the gastrointestinal tract. Cytochrome P450 3A is the more common form of cytochrome isoforms found in the intestine, but there are numerous examples that can inhibit, or induce, metabolism much in the same way that hepatic metabolism is affected by chemicals. In addition, the bacterial content of the gastrointestinal tract can affect the absorption of substances primarily by bacterial metabolism. The fasting status of the animal also will affect absorption, and is probably one the more important considerations in the design of a toxicology study. It has been clearly shown that absorption occurs more readily in the fasted animal, and that toxicity may be enhanced since there is a greater surface area of the gastrointestinal tract available for absorption. Finally, chemical interactions will potentially modify absorption through binding of the compound or changing the local cellular environment. From a practical perspective, oral administration of compounds is the most common method for compound administration in toxicology studies. In oral toxicity studies, one will need to consider the drug formulation and the potential effects of the vehicle on the stability as well as the potential toxicity of the vehicle. For the most part, a majority of the vehicles being used currently in laboratories have a long history of use such that toxicity of the vehicle does not become too much of a concern, but the principle of toxicology, the dose makes the poison, should always be a consideration.

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Peptidyl-urea based inhibitors of soluble epoxide hydrolases

Morisseau

Newman

Tsai

et al. 2006

Bioorganic & Medicinal Chemistry Letters

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We prepared a series of amino acid derived cyclohexyl and adamantyl ureas and tested them as inhibitors of the human soluble epoxide hydrolase, and obtained very potent compounds (K I = 15 nM) that are >10-fold more soluble than previously described sEH inhibitors. While our lead compound 2 showed low apparent bioavailability in dogs and rats, this series of compounds revealed that sEH inhibitor structures could accept large groups that could lead to better orally available drugs. Keywords Cardiovascular diseases; Soluble epoxide hydrolase inhibitorsSoluble epoxide hydrolase (sEH; EC 3.3.3.2) catalyzes the addition of a water molecule to an epoxide resulting in the corresponding diol. 1 Endogenous substrates for sEH include epoxyeicosatrienoic acids (EETs), which are known for their vasodilatory effects as well as for their anti-inflammatory actions. 2 Hydrolysis of the epoxides by sEH diminished this activity. 3 The inhibition of sEH led to the accumulation of EETs and other lipid epoxides in the organism. 4 Furthermore, sEH inhibition in rodent models can successfully treat hypertension, 4b,5 and inflammatory diseases, 6 as well as protect against renal damage caused by hypertension. 7The development in our laboratory of novel, stable, highly potent, and selective inhibitors for sEH 4a has allowed the elucidation of the biology associated with sEH. 1,2d Crystal structure determinations show that the urea inhibitors establish hydrogen bonding and salt bridges between the urea function of the inhibitor and residues of the sEH active site. 8 However, these dialkyl-ureas have high crystal lattice energies as indicated by their high melting point, and also have limited solubility in water, 4 likely affecting their in vivo efficacy. While medicinal chemistry approaches were used to increase their inhibitory activity and solubility, 9 the latest compounds reported may not possess physical properties consistent with successful pharmaceutical candidates. 10 Therefore, there remains a need for novel sEH inhibitor structures with improved biological availability and stability for possible future orally administered in vivo drugs. There is also the need for synthetic methods amenable to high throughput combinatorial or parallel methods.As shown previously, if placed at an appropriate distance from the urea moiety polar groups can be incorporated into one of the alkyl groups of the dialkyl-urea sEH inhibitors without loss of activity. 9 Such modifications give the new inhibitors better solubility and availability; however, only straight alkyl chain derivatives such as 12-(3-adamantyl-ureido)-dodecanoic acid (AUDA; see Fig. 1 that while the catalytic tunnel is restricted around the catalytic residues it enlarges as one moves away from the site of reaction to yield relatively large cavities. These structural features suggest that the enzyme could accommodate branches on the main alkyl chain. To evaluate a wide variety of side chains, we used a semi-combinatorial approach. Because amino acids are simple bifunctional s...

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Improved Intestinal Transport of PD 158473, an N-methyl-d-Aspartate (NMDA) Antagonist, by Involvement of Multiple Transporters

Cited by 6 publications

References 21 publications

Anatomical and Physiological Factors Affecting Oral Drug Bioavailability in Rats, Dogs, and Humans

Anatomical and Physiological Factors Affecting Oral Drug Bioavailability in Rats, Dogs, and Humans

Peroral Toxicity

Peptidyl-urea based inhibitors of soluble epoxide hydrolases

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