Why is it Challenging to Predict Intestinal Drug Absorption and Oral Bioavailability in Human Using Rat Model

Cao, Xianhua; Gibbs, Seth; Fang, Lanyan; Miller, Heather A.; Landowski, Christopher P.; Shin, Ho‐Chul; Lennernäs, Hans; Zhong, Yanqiang; Amidon, Gordon L.; Yu, Lawrence X.; Sun, Duxin

doi:10.1007/s11095-006-9041-2

Cited by 339 publications

(271 citation statements)

References 68 publications

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“…However, it is generally accepted that the absorptive transporters ASBT, MRP3, MCT1, OATP2B1 and OSTa/b have moderate to high intestinal expression levels. [12,[14][15][16]18,20,21,29,32,33,36,39,40] The three known intestinal exsorptive transporters for organic anions (BCRP, MRP2 and OSTa/b) all have relatively high expression levels -especially BCRP has a high intestinal expression compared with other tissues. [14,16,18,20,21,23,39] A high transporter expression level is likely indicative of an important role in the absorption or elimination of endogenous and exogenous substances.…”

Section: Intestinal Transporters For Organic Anions and Their Substramentioning

confidence: 99%

“…Jejunum > colon [14] Colon > ileum, not in jejunum [24] MRP1 ABCC1 Ab Jejunum = ileum = colon [27] Jejunum, ileum > duodenum [28] Jejunum = colon [14] Duodenum [19] Jejunum [20] Small intestine [21,29] Colon [29,30] Small intestine and colon [31] Too low expression in jejunum, ileum and colon for protein determination [29] MRP2 ABCC2 Ex Jejunum > ileum > > colon [27] Duodenum > ileum > > colon [32] Duodenum = ileum > colon [16] Jejunum, ileum > duodenum [28] Duodenum > > colon [33] Jejunum > colon [18] Duodenum [19] Jejunum [16,20] Small intestine [21] Jejunum > ileum = colon [27] MRP3 ABCC3 Ab Colon > Ileum = duodenum [16] Jejunum, ileum > duodenum [28] Colon > jejunum [18] Duodenum [19] Jejunum [16,20] Small intestine [21,32] Colon [28,32] Small intestine and colon [29] MRP4 ABCC4 N.R. Jejunum, ileum > duodenum [28] Jejunum = colon [14] Jejunum [20] Small intestine [21,32] Colon [28,32] N.R.…”

Section: Intestinal Transporters For Organic Anions and Their Substramentioning

confidence: 99%

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Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Grandvuinet

Vestergaard

Rapin³

et al. 2012

Journal of Pharmacy and Pharmacology

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Objectives This review provides an overview of intestinal human transporters for organic anions and stresses the need for standardization of the various in‐vitro methods presently employed in drug–drug interaction (DDI) investigations. Key findings Current knowledge on the intestinal expression of the apical sodium‐dependent bile acid transporter (ASBT), the breast cancer resistance protein (BCRP), the monocarboxylate transporters (MCT) 1, MCT3‐5, the multidrug resistance associated proteins (MRP) 1–6, the organic anion transporting polypetides (OATP) 2B1, 1A2, 3A1 and 4A1, and the organic solute transporter α/β (OSTα/β) has been covered along with an overview of their substrates and inhibitors. Furthermore, the many challenges in predicting clinically relevant DDIs from in‐vitro studies have been discussed with focus on intestinal transporters and the various methods for deducting in‐vitro parameters for transporters (Km/Ki/IC50, efflux ratio). The applicability of using a cut‐off value (estimated based on the intestinal drug concentration divided by the Ki or IC50) has also been considered. Summary A re‐evaluation of the current approaches for the prediction of DDIs is necessary when considering the involvement of other transporters than P‐glycoprotein. Moreover, the interplay between various processes that a drug is subject to in‐vivo such as translocation by several transporters and dissolution should be considered.

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Section: Intestinal Transporters For Organic Anions and Their Substramentioning

confidence: 99%

Section: Intestinal Transporters For Organic Anions and Their Substramentioning

confidence: 99%

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Grandvuinet

Vestergaard

Rapin³

et al. 2012

Journal of Pharmacy and Pharmacology

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“…There are likely to be some differences in the enzyme activities of the CYP2C and 3A subfamilies between rats and humans [27] . The protein homologies between CYP2C and 3A in rats and humans have been reported to be very similar, 73% and 77%, respectively [28] .…”

Section: Discussionmentioning

confidence: 99%

Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in rats

Yang

Cho

2011

Acta Pharmacol Sin

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npg IntroductionLosartan (DuP 753,, an angiotensin II receptor antagonist, has a low side-effect profile and is approved for the treatment of hypertension, alone or in combination with other agents [1] . After oral administration, losartan is almost completely absorbed and extensively metabolized to a carboxylic acid derivative, EXP-3174, mainly by cytochrome P450 (CYP) 2C9 and 3A4 [2] . EXP-3174 is a major active metabolite in both rats and humans and is a more potent inhibitor of angiotensin II receptor than losartan, with high-affinity receptor specificity [3] . Losartan has also been reported to be a substrate of P-glycoprotein (P-gp) [4] . Considering that losartan is a substrate of both CYP enzymes and P-gp, the modulation of CYP and P-gp activities may cause significant changes in the pharmacokinetic profiles of losartan and its active metabolite, EXP-3174.Ticlopidine, a potent antiplatelet agent induced by adenosine diphosphate, is used for the treatment of a variety of platelet-dependent disease states [5] . Several papers recommend ticlopidine as a valuable alternative when patients cannot tolerate aspirin [6,7] . It has been reported that ticlopidine causes significant inhibition of several drugs metabolized by the hepatic CYP enzyme system [8,9] .Clinically, losartan and ticlopidine can be prescribed concomitantly for the prevention or therapy of cardiovascular diseases. However, the pharmacokinetic interaction between ticlopidine and losartan in vivo has not yet been reported. Therefore, the present study aimed to evaluate the effect of ticlopidine on the pharmacokinetics of losartan and its active metabolite, EXP-3174, in rats. The effects of ticlopidine on P-gp, CYP2C9, and 3A4 activities were also evaluated. Materials and methods ChemicalsLosartan, EXP-3174, L-158.809 (internal standard), acetonitrile, methanol, and tert-butylmethylether were purchased from Merck Corporation (Darmstadt, Germany). Ticlopidine was purchased from Sigma-Aldrich Corporation (St Louis, MO, USA). All other chemicals were of reagent grade, and all solvents were of HPLC grade. Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in ratsSi-hyung YANG 1 , Young-ah CHO 2 , Jun-shik CHOI 3, * Aim: Losartan and antiplatelet agent ticlopidine can be prescribed concomitantly for prevention or therapy of cardiovascular diseases. Hence, the effects of ticlopidine on the pharmacokinetics of losartan and its active metabolite EXP-3174 were evaluated in rats. Methods: Ticlopidine (4 or 10 mg/kg po) was administered 30 min before administration of losartan (9 mg/kg po or 3 mg/kg iv). The activity of human CYP2C9 and 3A4 were measured using the CYP inhibition assay kit. The activity of P-gp was evaluated using rhodamine-123 retention assay in MCF-7/ADR cells. Results: Ticlopidine (10 mg/kg) significantly increased the areas under the plasma concentration-time curves (AUCs) and peak plasma concentration (C max ) of oral losartan (9 mg/kg), as well as the AUCs of the active metabolite EXP-3174. Ticlopid...

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“…3) [26]. Охарактеризован и ряд других белков-транспортеров (MRP3, PepT1, SGLT-1, NT2, GLUT1, GLUT3, GLUT5) [27]. Все они специфичны к широким группам лекарственных веществ, в основном в зависимости от степени гидрофобности/гидрофильности последних.…”

Section: влияние клеточных процессов в энтероците 2221 роль белкunclassified

“…Cао с соавт. [27] сравнили параметры, влияющие на биодоступность, для 48 лекарственных препаратов (включая верапамил, валацикловир, аминокислоты, пропранолол, фуросемид и др. ), часть из которых абсорбируется путём пассивного транспорта, часть -через транспортеры, часть -и тем и другим способом.…”

Section: рисунок4unclassified

Bioavailability of oral drug formulations and methods for its improvement

et al. 2010

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The recent studies in nanotechnology resulted in the development of novel formulations with improved bioavailability. This is especially important for oral administered drugs as the most convenient formulations. The current review deals with the processes occurring at the gastro-intestinal (GI) tract and their influence on the drug form. The increase of bioavailability of the drug may be achieved through designing novel formulations according to the specific drug properties. They include capsules that release pharmaceutical agents at various parts of the GI tract, floating systems that prolong the presence of the drug in the GI tract, dispersed forms with surface-active soluble polymers, micelles that carry poor-soluble drugs inside their non-polar core, agents that facilitate tight junction opening, such as caprate and chitosan, and lipid-based formulations. The own data show the stimulating influence of phospholipid nanoparticles on peroral absorption of drug indomethacin in rats and on passage of transport marker and drugs through Caco-2 cell monolayer in vitro. The review summarizes current understanding of factors that influence the bioavailability of the oral drug forms, currently used models for pharmacokinetic studies, and various approaches to developing novel pharmaceutical forms that increase the bioavailability of the drugs.

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Why is it Challenging to Predict Intestinal Drug Absorption and Oral Bioavailability in Human Using Rat Model

Cited by 339 publications

References 68 publications

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in rats

Bioavailability of oral drug formulations and methods for its improvement

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