Multiple transport mechanisms involved in the intestinal absorption and first-pass extraction of fexofenadine,

Tannergren, Christer; Petri, Niclas; Knutson, Lars; Hedeland, Mikael; Bondesson, Ulf; Lennernäs, Hans

doi:10.1016/s0009-9236(03)00238-8

Cited by 81 publications

(92 citation statements)

References 43 publications

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“…The E H is dependent on the blood flow (Qh), protein binding (fu) and intrinsic clearance of the enzymes or transporters (Clint) (Rowland & Tozer 1995). Recently, it has also been recognized that membrane transport into the hepatocyte has to be included in the models for predicting and explaining liver extraction (Tannergren et al 2003a;Chandra & Brouwer 2004).…”

Section: Introductionmentioning

confidence: 99%

The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension

Lennernäs

Abrahamsson

2005

Journal of Pharmacy and Pharmacology

184

119

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Bioavailability (BA) and bioequivalence (BE) play a central role in pharmaceutical product development and BE studies are presently being conducted for New Drug Applications (NDAs) of new compounds, in supplementary NDAs for new medical indications and product line extensions, in Abbreviated New Drug Applications (ANDAs) of generic products and in applications for scale-up and post-approval changes. The Biopharmaceutics Classification System (BCS) has been developed to provide a scientific approach for classifying drug compounds based on solubility as related to dose and intestinal permeability in combination with the dissolution properties of the oral immediaterelease (IR) dosage form. The aim of the BCS is to provide a regulatory tool for replacing certain BE studies by accurate in-vitro dissolution tests. The aim of this review is to present the status of the BCS and discuss its future application in pharmaceutical product development. The future application of the BCS is most likely increasingly important when the present framework gains increased recognition, which will probably be the case if the BCS borders for certain class II and III drugs are extended. The future revision of the BCS guidelines by the regulatory agencies in communication with academic and industrial scientists is exciting and will hopefully result in an increased applicability in drug development. Finally, we emphasize the great use of the BCS as a simple tool in early drug development to determine the rate-limiting step in the oral absorption process, which has facilitated the information between different experts involved in the overall drug development process. This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in drug molecules with a sufficiently high permeability, solubility and dissolution rate, and that will automatically increase the importance of the BCS as a regulatory tool over time.

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Section: Introductionmentioning

confidence: 99%

The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension

Lennernäs

Abrahamsson

2005

Journal of Pharmacy and Pharmacology

184

119

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“…Previous studies conducted by our group showed reduction of the p.o. area under the blood-concentration time curve (AUC) for fexofenadine [P-gp, OATP substrate (Cvetkovic et al, 1999;Tannergren et al, 2003;Shimizu et al, 2005;Kikuchi et al, 2006;Bailey et al, 2007)] in the presence of GF120918 (P-gp inhibitor) in the rat with concomitant dosing of RIF [OATP inhibitor (Vavricka et al, 2002;Garver et al, 2006)], so RIF was selected as a model Oatp inhibitor in the present studies. Additional in vivo studies were conducted to explore whether RIF administration reduced macrolide p.o.…”

mentioning

confidence: 99%

Involvement of Intestinal Uptake Transporters in the Absorption of Azithromycin and Clarithromycin in the Rat

Garver¹,

Hugger²,

Shearn³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Macrolide antibiotics azithromycin (AZI) and clarithromycin (CLARI) are large molecular weight compounds and are substrates for apically polarized efflux transporters such as P-glycoprotein, which can potentially restrict intestinal absorption. However, despite these undesired physicochemical and biopharmaceutical properties, AZI and CLARI exhibit moderate to excellent p.o. bioavailability in preclinical species and humans. Intestinal uptake transporters, such as organic anion transporting polypeptides (OATPs), can facilitate the uptake of drugs that are substrates and hence increase p.o. absorption. The present study was designed to determine whether the intestinal Oatps are involved in absorption of these macrolides. Macrolide antibiotics azithromycin (AZI) and clarithromycin (CLARI) are predicted by Lipinski's "rule of 5" (Lipinski et al., 1997) to have poor permeation or absorption because of their large molecular weight and hydrogen bonding potential; however, these macrolides show moderate to excellent p.o. exposure in preclinical species and humans. For example, AZI exhibits 46, 97, and 37% p.o. bioavailability in rats, dogs (Shepard and Faulkner, 1990), and humans (Foulds et al., 1990), respectively, even though AZI does not conform to Lipinski rules with its molecular mass of 749 Da, 5 H-bond donors, and 14 H-bond acceptors (Lipinski et al., 1997). Lipinski et al. (1997) suggest that some therapeutic classes such as antibiotics contain orally active drugs because they are substrates for naturally occurring transporters. Both macrolides have been reported to be substrates for the apically polarized efflux transporter P-glycoprotein (P-gp), which can restrict intestinal permeation (Pachot et al., 2003;Sugie et al., 2004). The biliary and intestinal excretion of AZI in the rat has been reported to be mediated by P-gp and multidrug resistance-associated protein 2 (Sugie et al., 2004). CLARI has also been reported to be an inhibitor of CYP3A4 and P-gp (Sugie et al., 2004). Although the metabolism, distribution, and excretion pathways have been investigated for AZI and CLARI, the mechanism of intestinal absorption for these macrolides has not been fully investigated.The organic anion transporting polypeptides (OATPs) comprise a superfamily of sodium-independent transporters that facilitate the transport of endogenous compounds and structurally diverse xenobiotics (Kim, 2003;Hagenbuch and Meier, 2004). These transporters are widely distributed throughout the body, particularly in tissues responsible for mediating the absorption, distribution, metabolism, and excretion properties of drugs, such as the liver, kidney, brain, and intestine (Tamai et al., 2000). OATPs within the same family (e.g., OATP1, OATP2) share Ն40% amino acid sequence identities, whereas members in the same subfamily (e.g., OATP1A, OATP1B) have Ն60% amino acid sequence identities (Hagenbuch and Meier, 2004). Currently, 11 human OATPs and 14 rat Oatps have been identified (Marzolini et al., 2004). In humans, OATP1B1 (or OATP-C) and O...

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“…Earlier in vitro results have shown that fexofenadine is transported by various mechanisms across biological membranes, including transcellular passive diffusion and, to some extent, P-glycoprotein (ABCB1) and organic anion-transporting polypeptides (OATPs) (Cvetkovic et al, 1999;Dresser et al, 2002;Perloff et al, 2002;Kobayashi et al, 2003;Nozawa et al, 2004;Petri et al, 2004). Several clinical studies have reported drug-drug and drug-diet interactions between fexofenadine and substrates or inhibi-tors of both these transporters (Davit et al, 1999;Hamman et al, 2001;Dresser et al, 2002;Wang et al, 2002;Tannergren et al, 2003b).…”

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confidence: 99%

“…However, the study conducted with verapamil demonstrated that the systemic exposure of fexofenadine increased 4-fold in the presence of the inhibitor (Tannergren et al, 2003b). It was suggested that this result could be related to inhibition of verapamil on the OATP-mediated liver uptake from the sinusoids and/or secretion of canalicular ABCB1 into the bile (Cvetkovic et al, 1999;Perloff et al, 2002;Petri et al, 2004).…”

mentioning

confidence: 99%

First-Pass Effects of Verapamil on the Intestinal Absorption and Liver Disposition of Fexofenadine in the Porcine Model

Petri¹,

Bergman²,

Forsell³

et al. 2006

Drug Metab Dispos

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ABSTRACT:The aim of this study in pigs was to investigate the local pharmacokinetics of fexofenadine in the intestine and liver by using the pig as a model for drug transport in the entero-hepatobiliary system. A parallel group design included seven pigs (10-12 weeks, 22.2-29.5 kg) in three groups (G1, G2, G3), and a jejunal single-pass perfusion combined with sampling from the bile duct and the portal, hepatic, and superior caval veins was performed. Fexofenadine was perfused through the jejunal segment alone (G1: 120 mg/l, total dose 24 mg) or with two different verapamil doses (G2: 175 mg/l, total dose 35 mg; and G3: 1000 mg/l, total dose 200 mg). The animals were fully anesthetized and monitored throughout the experiment. Fexofenadine had a low liver extraction (E H ; mean ؎ S.E.M.), and the given doses of verapamil did not affect the E H (0.13 ؎ 0.04, 0.16 ؎ 0.03, and 0.12 ؎ 0.02 for G1, G2, and G3, respectively) or biliary clearance. The E H for verapamil and antipyrine agreed well with human in vivo data. Verapamil did not increase the intestinal absorption of fexofenadine, even though the jejunal permeability of fexofenadine, verapamil, and antipyrine showed a tendency to increase in G2. This combined perfusion and hepatobiliary sampling method showed that verapamil did not affect the transport of fexofenadine in the intestine or liver. In this model the E H values for both verapamil and antipyrine were similar to the corresponding values in vivo in humans.The effect of carrier-mediated membrane transport on absorption, first-pass liver extraction, distribution and elimination is not established, because the exact in vivo transport mechanism(s) and its relevance for many drugs that are transport substrates is far from completely understood. Although our knowledge in the field has greatly increased, the integral view on the practical implications of the related findings for ADME research lacks the relevant human in vivo data and a stringent use of data from in vitro models (Meijer and Lennernas, 2005). In addition, investigations of the local liver exposure of drugs and metabolites are considered to be important when assessing dose-dependent drug-induced hepatoxicity (Lee, 2003). Consequently, a model enabling direct determinations to be made of the in vivo kinetics of intestinal and hepatobiliary transport and the metabolism of drugs would be a valuable tool. The use of such a model should increase the understanding of the mechanisms underlying the processes determining the bioavailability and local liver exposure and have an impact on pharmacokinetics and the safety evaluation of drugs. This article describes a novel pig model that combines an intestinal perfusion technique, previously validated in vivo in humans (Lennernas et al., 1992), with sampling from the portal and hepatic vein and bile collection.The transport of a compound across biological membranes often involves multiple transport mechanisms. Hence, the intestinal absorption and disposition of drugs and metabolites is a complex process, gove...

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Multiple transport mechanisms involved in the intestinal absorption and first-pass extraction of fexofenadine,

Cited by 81 publications

References 43 publications

The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension

The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension

Involvement of Intestinal Uptake Transporters in the Absorption of Azithromycin and Clarithromycin in the Rat

First-Pass Effects of Verapamil on the Intestinal Absorption and Liver Disposition of Fexofenadine in the Porcine Model

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