Altered drug disposition of the platelet activating factor antagonist apafant in mdr1a knockout mice

Leusch, Andreas; Volz, Astrid; Müller, Gabriele; Wagner, Andrea; Sauer, Achim; Greischel, Andreas; Roth, Willy

doi:10.1016/s0928-0987(02)00088-x

Cited by 17 publications

(16 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mean BPR of dantrolene in wild-type rats was 0.042 6 0.016, increased 3.7-fold in Bcrp knockouts (0.156 6 0.010) and 3.9-fold in double Mdr1a/Bcrp knockouts (0.163 6 0.024), but was unchanged in the Mdr1a knockout rat group (0.047 6 0.009). Plasma and brain concentration data are given in Supplemental Table 1. WEB 2086 was selected as a P-gp substrate because its P-gp-dependent brain penetration has already been demonstrated in vivo using Mdr1a knockout mice (Leusch et al, 2002). Dantrolene was chosen as a BCRP substrate because, in contrast to the majority of BCRP substrates, it is not or is only a weak substrate for P-gp in vitro and in vivo (Enokizono et al, 2008;Kodaira et al, 2010;Xiao et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

“…Normal Sprague-Dawley rats, which are the background for the knockout strains, were used as wild-type controls. As a P-gp substrate, the compound WEB 2086 (Leusch et al, 2002). Dantrolene was selected as a specific BCRP substrate based on data from in vitro and in vivo literature (Enokizono et al, 2008;Kodaira et al, 2010;Xiao et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Brain Penetration of WEB 2086 (Apafant) and Dantrolene in Mdr1a (P-Glycoprotein) and Bcrp Knockout Rats

et al. 2014

View full text Add to dashboard Cite

Transporter gene knockout rat models are attracting increasing interest for mechanistic studies of new drugs as transporter substrates or inhibitors in vivo. However, limited data are available on the functional validity of such models at the blood-brain barrier. Therefore, the present study evaluated Mdr1a [P-glycoprotein (P-gp)], Bcrp, and combined Mdr1a/Bcrp knockout rat strains for the influence of P-gp and breast cancer resistance protein (BCRP) transport proteins on brain penetration of the selective test substrates [ .5-fold in double Mdr1a/Bcrp knockouts, and 7.3-fold in zosuquidar-treated wild-type rats, but was unchanged in Bcrp knockout rats. Mean BPR of dantrolene increased 3.3-fold in Bcrp knockouts and 3.9-fold in double Mdr1a/Bcrp knockouts compared with wild type, but was unchanged in the Mdr1a knockouts. The human intestinal CaCo-2 cell bidirectional transport system in vitro confirmed the in vivo finding that [ 14 C]WEB 2086 is a substrate of P-gp but not of BCRP. Therefore, Mdr1a, Bcrp, and combined Mdr1a/Bcrp knockout rats provide functional absence of these efflux transporters at the blood-brain barrier and are a suitable model for mechanistic studies on the brain penetration of drug candidates.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Brain Penetration of WEB 2086 (Apafant) and Dantrolene in Mdr1a (P-Glycoprotein) and Bcrp Knockout Rats

et al. 2014

View full text Add to dashboard Cite

show abstract

“…[ 3 H]Digoxin (0.5 mg/kg) was administered intravenously into the tail vein at a single bolus dose (9.25 MBq/mg) using a formulation according to Leusch et al (2002).…”

mentioning

confidence: 99%

In Vitro to In Vivo Comparison of the Substrate Characteristics of Sorafenib Tosylate toward P-Glycoprotein

Gnoth¹,

Sandmann²,

Engel³

et al. 2010

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Sorafenib (Nexavar) is a novel oral Raf kinase and vascular endothelial growth factor receptor inhibitor. Most anticancer drugs are substrates for ATP-binding cassette efflux pumps especially for P-glycoprotein (P-gp). To evaluate the influence of P-gp on the pharmacokinetics of sorafenib substrate properties for this transporter were investigated. Therefore, permeability of sorafenib across Caco-2 and P-gp-overexpressing cells was determined. To determine the in vivo relevance of these in vitro findings, pharmacokinetics of sorafenib in mdr1a/1b(؊/؊) and wild-type (WT) mice was studied. Sorafenib is highly permeable and exhibits a slight efflux across Caco-2 cells. In P-gp-overexpressing cells, a small concentration-dependent efflux was observed, which was completely blocked by the addition of ivermectin. In mdr1a/1b(؊/؊) and WT mice, unchanged compound represented by far the majority of radioactivity in plasma. After intravenous and oral administration, brain/plasma concentration ratios in mdr1a/1b(؊/؊) mice were 1.3-to 1.5-fold higher than those in WT mice. However, after intravenous or oral administration, plasma concentrations were similar in both mouse strains. In conclusion, sorafenib is highly permeable and a weak P-gp substrate in vitro. These findings were confirmed by the small factor of 1.3 to 1.5 observed for the brain/plasma ratios in mdr1a/1b(؊/؊) versus WT mice in vivo. Based on these in vitro and in vivo results, it is unlikely that P-gp has a major effect on the plasma concentrations of sorafenib in humans. Because of the high permeability and low P-gp-mediated transport, sorafenib might be able to cross the blood-brain barrier and target tumors within the brain.

show abstract

“…Studies in our laboratory showed that the biliary excretion of compound 18 was reduced by 90% in Bcrp knockout mice (data not shown). P-gp-mediated secretion from the systemic circulation into the intestinal lumen has also been reported for several drugs, including apafant (Mayer et al, 1996;Sparreboom et al, 1997;Leusch et al, 2002). Apafant has passive permeability of approximately 10 ϫ 10 Ϫ6 cm/s and an efflux ratio of 9 in Caco-2 cells.…”

Section: Discussionmentioning

confidence: 87%

“…Apafant has passive permeability of approximately 10 ϫ 10 Ϫ6 cm/s and an efflux ratio of 9 in Caco-2 cells. After an intravenous administration of [ 14 C]apafant to bile duct-catheterized mice, intestinal excretion of radioactivity was 54.9 and 6.8% of the dose in wild-type and Mdr1a(Ϫ/Ϫ) mice, respectively (Leusch et al, 2002). The interplay between transporters and metabolic enzymes could influence the predictability of CL from in vitro metabolic CL int as well.…”

Section: Discussionmentioning

confidence: 99%

Relationship between Passive Permeability, Efflux, and Predictability of Clearance from In Vitro Metabolic Intrinsic Clearance

Huang¹,

Berry²,

Ganga³

et al. 2009

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:In vitro intrinsic metabolic clearance (CL int ) is used routinely for compound selection in drug discovery; however, in vitro CL int often underpredicts in vivo clearance (CL). Forty-one proprietary compounds and 16 marketed drugs were selected to determine whether permeability and efflux status could influence the predictability of CL from in vitro CL int obtained from liver microsomal and hepatocyte incubations. For many of the proprietary compounds examined, rat CL was significantly underpredicted using the well stirred model incorporating both fraction of unbound drug in blood and fraction of unbound drug in the microsomal or hepatocyte incubation. Further analysis revealed that the accuracy of the prediction was differentiated by permeability and P-glycoprotein-(Pgp) and mouse breast cancer resistance protein (mBcrp)-mediated efflux. For proprietary compounds with passive permeability greater than 5 ؋ 10 ؊6 cm/s and efflux ratios less than 5 in both P-gp-and mBcrp-expressing cells, CL int provided reasonable prediction. The average -fold error (AFE) was 1.8 for rat liver microsomes (RLMs) and 2.3 for rat hepatocytes. In contrast, CL was dramatically underpredicted for compounds with passive permeability less than 5 ؋ 10 ؊6 cm/s; AFEs of 54.4 and 29.2 were observed for RLM and rat hepatocytes, respectively. In vivo CL was also underpredicted for compounds that were good efflux substrates (permeability >5 ؋ 10 ؊6 cm/s). The AFEs were 7.4 and 8.1for RLM and rat hepatocytes, respectively. A similar relationship between permeability, efflux status, and human CL prediction reported in the literature was observed for 16 marketed drugs. These data show that permeability and efflux status are determinants for the predictability of CL from in vitro metabolic CL int .In vitro metabolic clearance (CL int ) derived from liver microsomal incubations is used routinely to aid compound selection in drug discovery. Hepatocytes, which possess intact cellular membranes, complete enzymatic systems, and cofactors, have also become a common option for determination of CL int . Successful prediction of in vivo clearance (CL) from CL int in liver microsomes or hepatocytes has been reported for some compounds. Obach (1999) reported that CL was predicted within a 2-fold error for 16 of 29 compounds from CL int in human liver microsomes using the well stirred model incorporating both fraction of unbound drug in blood (fu b ) and fraction of unbound drug in the microsomal or hepatocyte incubation (fu inc ).Likewise, CL int from human hepatocytes provided prediction within a 2-fold error for 11 of 37 (Brown et al., 2007) or 23 of 56 compounds (Riley et al., 2005). However, a tendency toward underprediction was observed for many drugs (Obach, 1999;Ito and Houston, 2004;Riley et al., 2005;Brown et al., 2007;Stringer et al., 2008). Marked underprediction of CL from in vitro metabolic CL int in humans and/or animals has been reported for compounds such as montelukast, troglitazone, and quinotolast (Naritomi et al., 2001(Naritomi e...

show abstract

Altered drug disposition of the platelet activating factor antagonist apafant in mdr1a knockout mice

Cited by 17 publications

References 20 publications

Brain Penetration of WEB 2086 (Apafant) and Dantrolene in Mdr1a (P-Glycoprotein) and Bcrp Knockout Rats

Brain Penetration of WEB 2086 (Apafant) and Dantrolene in Mdr1a (P-Glycoprotein) and Bcrp Knockout Rats

In Vitro to In Vivo Comparison of the Substrate Characteristics of Sorafenib Tosylate toward P-Glycoprotein

Relationship between Passive Permeability, Efflux, and Predictability of Clearance from In Vitro Metabolic Intrinsic Clearance

Contact Info

Product

Resources

About