MDR1-deficient genotype in Collie dogs hypersensitive to the P-glycoprotein substrate ivermectin

Roulet, Alain; Puel, Olivier; Gesta, Stéphane; Lepage, Jean‐François; Drag, Marlene; Soll, M. D.; Alvinerie, M.; Pineau, Thierry

doi:10.1016/s0014-2999(02)02955-2

Cited by 129 publications

(124 citation statements)

References 20 publications

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“…These results were consistent with the high MDR1/Pgp expression in brain capillary cells and suggested that MDR1/Pgp plays a predominant role in the blood-brain barrier of mice. Interestingly, the well-known sensitivity of inbred dogs, such as collies and Australian shepherds, to ivermectin was also linked to a 4-bp deletion mutation resulting in a frame-shift and a lack of canine MDR1/Pgp expression (296). On the other hand, ivermectin is widely used to treat river blindness (onchocerciasis) in Africa.…”

Section: Physiological and Pharmacological Functions Of Mdr1/pgpmentioning

confidence: 99%

Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System

Sarkadi¹,

Homolya²,

Szakács³

et al. 2006

Physiological Reviews

642

532

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In this review we give an overview of the physiological functions of a group of ATP binding cassette (ABC) transporter proteins, which were discovered, and still referred to, as multidrug resistance (MDR) transporters. Although they indeed play an important role in cancer drug resistance, their major physiological function is to provide general protection against hydrophobic xenobiotics. With a highly conserved structure, membrane topology, and mechanism of action, these essential transporters are preserved throughout all living systems, from bacteria to human. We describe the general structural and mechanistic features of the human MDR-ABC transporters and introduce some of the basic methods that can be applied for the analysis of their expression, function, regulation, and modulation. We treat in detail the biochemistry, cell biology, and physiology of the ABCB1 (MDR1/P-glycoprotein) and the ABCG2 (MXR/BCRP) proteins and describe emerging information related to additional ABCB- and ABCG-type transporters with a potential role in drug and xenobiotic resistance. Throughout this review we demonstrate and emphasize the general network characteristics of the MDR-ABC transporters, functioning at the cellular and physiological tissue barriers. In addition, we suggest that multidrug transporters are essential parts of an innate defense system, the “chemoimmunity” network, which has a number of features reminiscent of classical immunology.

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Section: Physiological and Pharmacological Functions Of Mdr1/pgpmentioning

confidence: 99%

Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System

Sarkadi¹,

Homolya²,

Szakács³

et al. 2006

Physiological Reviews

642

532

View full text Add to dashboard Cite

show abstract

“…None of them resulted in a complete loss of transport. This, however, was observed when a deletion mutation was found to occur frequently in the Collie dog MDR1 gene (Mealey et al 2001;Roulet et al 2003;Geyer et al 2005a,b). These dogs suffer from neurotoxic symptoms of the antiparasitic drugs ivermectin and moxidectin that normally do not reach the central nervous system (Geyer et al 2005a).…”

Section: Drug Carrier Polymorphisms and Pathologiesmentioning

confidence: 99%

Drug transporters in pharmacokinetics

Petzinger¹,

Geyer²

2006

Naunyn Schmied Arch Pharmacol

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This review deals with the drug transporters allowing drugs to enter and leave cells by carrier-mediated pathways. Emphasis is put on liver transporters but systems in gut, kidney, and blood-brain barrier are mentioned as well. Drug-drug interactions on carriers may provoke significant modification in pharmacokinetics as do carrier gene polymorphisms yielding functional carrier protein mutations. An integrated phase concept should reflect the interplay between drug metabolism and drug transport.

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“…Ivermectin is a highly lipophilic endectocidal agent that readily crosses the BBB, but a Pglycoprotein mediated efflux mechanism helps to pump out the molecule from the CSF (Schinkel, 1999). Some dog breeds (Collie, Sheltie, Australian Shepherd) however, carry a mutated MDR-1 gene encoding a false P-glycoprotein (Roulet et al, 2003) thereby causing disturbances in this efflux mechanism in sensitive individuals. Selamectin, a derivative of ivermectin is tolerated better thus can also be used in MDR-1 mutant dog patients (Geyer et al 2009).…”

Section: Drug Distributionmentioning

confidence: 99%

Comparative Veterinary Pharmacokinetics

Jerzsele¹

2012

Readings in Advanced Pharmacokinetics - Theory, Methods and Applications

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MDR1-deficient genotype in Collie dogs hypersensitive to the P-glycoprotein substrate ivermectin

Cited by 129 publications

References 20 publications

Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System

Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System

Drug transporters in pharmacokinetics

Comparative Veterinary Pharmacokinetics

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