Enhanced Intestinal Absorption of Drugs by Activation of Peptide Transporter PEPT1 Using Proton‐Releasing Polymer

Nozawa, Takashi; Toyobuku, Hidekazu; Kobayashi, Daisuke; Kuruma, Keiko; Tsuji, Akira; Tamai, Ikumi

doi:10.1002/jps.10491

Cited by 47 publications

(20 citation statements)

References 33 publications

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“…These observations of the increased absorption of ester prodrugs suggest that the intestinal uptake/influx transporters are involved in the intestinal membrane permeation and determine the success of prodrug approach. We have experimentally showed the application of PEPT1 for oral deliver by three strategies depending on the chemical structures of the pharmacologically active drugs [4][5][6]. Compared with PEPT1, structural requirements as substrates of OATPs are not easy to clarify due to the broad selectivity, but they have more potential to be applied for variable compounds.…”

Section: : Perspective Of Oatp-mediated Oral Deliverymentioning

confidence: 99%

Oral drug delivery utilizing intestinal OATP transporters

Tamai

2012

Advanced Drug Delivery Reviews

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Abstract.Transporters play important roles in tissue distribution and urinary-and biliary-excretion of drugs and transporter molecules involved in those processes have been elucidated well. Furthermore, an involvement of efflux transporters such as P-glycoproteins, multidrug resistance associated protein 2, and breast cancer resistance protein as the intestinal absorption barrier and/or intestinal luminal secretion mechanisms has been demonstrated. However, although there are many suggestions for the contribution of uptake/influx transporters in intestinal absorption of drugs, information on the transporter molecules responsible for the intestinal absorptive process is limited. Among them, most studied absorptive drug transporter is peptide transporter PEPT1. However, utilization of PEPT1 for oral delivery of drugs may not be high due to the chemical structural requirement of PEPT1 limited to peptide-mimetics. Recently, organic anion transporting polypeptide (OATP) family such as OATP1A2 and OATP2B1 has been suggested to mediate intestinal absorption of several drugs. Since OATPs exhibit species difference in expressed tissues and functional properties between human and animals, human studies are essential to clarify the intestinal absorption mechanisms of drugs via OATPs. Recent pharmacogenomics studies demonstrated that OATP2B1 is involved in the drug absorption in human. In addition, information of drug-juice interaction in the intestine also uncovered the contribution of OATP1A2 and OATP2B1 in drug absorption. Since OATP1A2 and OATP2B1 exhibit broader substrate selectivity compared with PEPT1, their potential to be applied for oral delivery should be high. In this review, current understanding of characteristics and contribution as the absorptive transporters of OATPs in small intestine in human is described. Now, it is getting clearer that OATPs have significant roles in intestinal absorption of drugs, therefore, there are higher possibility to utilize OATPs as the tools for oral delivery.

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Section: : Perspective Of Oatp-mediated Oral Deliverymentioning

confidence: 99%

Oral drug delivery utilizing intestinal OATP transporters

Tamai

2012

Advanced Drug Delivery Reviews

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144

105

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“…It is reported that a proton releasing polymer, Eudragit L100-55, can improve the permeability via PEPT1 because PEPT1 uses a proton-gradient as a driving force. 48 Acyclovir ACV is an antiviral drug used to treat infections primarily caused by herpes viruses, such as genital herpes, cold sores, shingles, and chicken pox. ACV is categorized as a BCS class III and class IV drug depending on the oral doses of ACV.…”

Section: Peptide Transportermentioning

confidence: 99%

A Minireview: Usefulness of Transporter-Targeted Prodrugs in Enhancing Membrane Permeability

Murakami

2016

Journal of Pharmaceutical Sciences

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Orally administered drugs are categorized into 4 classes depending on the solubility and permeability in a Biopharmaceutics Classification System. Prodrug derivatization is one of feasible approaches in modifying the physicochemical properties such as low solubility and low permeability without changing the in vivo pharmacological action of the parent drug. In this article, prodrug-targeted solute carrier (SLC) transporters were searched randomly by PubMed. Collected SLC transporters are amino acid transporter 1, bile acid transporter, carnitine transporter 2, glucose transporter 1, peptide transporter 1, vitamin C transporter 1, and multivitamin transporter. The usefulness of transporter-targeted prodrugs was evaluated in terms of membrane permeability, stability under acidic condition, and conversion to the parent drug. Among prodrugs collected, peptide transporter-targeted prodrugs exhibited the highest number, and some prodrugs such as valaciclovir and valganciclovir are clinically available. ATP-binding cassette efflux transporter, P-glycoprotein (P-gp), reduces the intestinal absorption of lipophilic P-gp substrate drugs, and SLC transporter-targeted prodrugs of P-gp substrate drugs circumvented the P-gp-mediated efflux transport. Thus, SLC transporter-targeted prodrug derivatization seems to be feasible approach to increase the oral bioavailability by overcoming various unwanted physicochemical properties of orally administered drugs, although the effect of food on prodrug absorption should be taken into consideration.

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“…However, some of these excipients have been found to alter drug absorption in vivo or in vitro (59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76). In addition to the potential influence on drug solubility and/or intestinal permeability, plausible mechanisms for these excipient effects may include change in the GI transit time or pH, inhibition or induction of metabolizing enzymes and/or transporters in the GI membrane, alteration of in vivo dissolution rate, complexation and/or degradation in GI lumen (59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76). The effects of some excipients, e.g., sorbitol and polysorbate 80, on drug absorption have been shown to depend on the amount of these excipients present in the formulation (75,76).…”

Section: Pharmaceutical and Biopharmaceutical Considerationsmentioning

confidence: 99%

Equivalence-by-Design: Targeting In Vivo Drug Delivery Profile

Chen

Lee

2008

Pharm Res

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In the United States (U.S.), drug products are considered therapeutically equivalent if they meet regulatory criteria of pharmaceutical equivalence and bioequivalence. These requirements can be traced back to 1977 when the U.S. Food and Drug Administration (FDA) published the regulations on bioavailability and bioequivalence. Over the years, to keep up with the advancement in science and technology, the FDA has been constantly updating the regulatory approaches to assessing and ensuring equivalence. In view of the recent growth in novel pharmaceutical dosage forms and delivery systems, this paper examines the current framework for documentation of therapeutic equivalence and explores the opportunities of further advancing equivalence methods for complex drug products. It is proposed that equivalence may be established by matching the in vivo drug delivery profile (iDDP) between drug products in comparison. This can be achieved by characterizing the iDDP of the reference formulation with application of an equivalence-by-design approach for pharmaceutical development. Critical variables can be identified to serve as in vitro markers or biomarkers for mapping the desired drug delivery profile in vivo. A multidisciplinary approach may be necessary to develop these markers for characterization of iDDPs.

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Enhanced Intestinal Absorption of Drugs by Activation of Peptide Transporter PEPT1 Using Proton‐Releasing Polymer

Cited by 47 publications

References 33 publications

Oral drug delivery utilizing intestinal OATP transporters

Oral drug delivery utilizing intestinal OATP transporters

A Minireview: Usefulness of Transporter-Targeted Prodrugs in Enhancing Membrane Permeability

Equivalence-by-Design: Targeting In Vivo Drug Delivery Profile

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