Implications of ABC transporters on the disposition of typical veterinary medicinal products

Schrickx, Jan A.; Fink‐Gremmels, Johanna

doi:10.1016/j.ejphar.2008.03.014

Cited by 63 publications

(57 citation statements)

References 144 publications

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“…6,7,10,35,42,47 Moreover, our results must be interpreted with caution. An association does not prove a cause and effect relationship, and falsepositive association (type I error) because of population stratification is possible even if care is taken in choosing unrelated cases and controls at the parental level.…”

Section: Discussionmentioning

confidence: 93%

“…28 In humans, the drug transporter hypothesis of pharmacoresistant epilepsy has been intensely investigated in recent years based on the hypothesis that localized overexpression of certain transporters proteins, such as P-gp would compromise the efficacy of AEDs by limiting their capacity to penetrate the BBB and reach their intended site of action. 6,10,14,15,20,[29][30][31][32] Typically, patients are resistant to 10,31,33 Altered interactions between P-gp and its substrates, including PB, were shown to be associated with ABCB1 gene polymorphisms in humans. 16 A study using a canine osteosarcoma cell line with Pgp overexpression evaluated the affinity of canine P-gp for a number of commonly used AEDs and reported PB as a weak substrate for canine P-gp.…”

Section: Discussionmentioning

confidence: 99%

“…The ABCB1 gene in dogs is located on chromosome 14 and includes 28 exons. 10,11 The protein, which functions as an ATP-dependent drug efflux pump in the BBB, supports a physiologic defense mechanism extruding a very wide variety of compounds that are potentially toxic to the central nervous system (CNS), 10,[12][13][14][15] including AEDs such as PB. 16,17 Dysfunction of this neuroprotective protein may lead to either CNS intoxication or drug resistance.…”

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confidence: 99%

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Polymorphisms in the ABCB1 Gene in Phenobarbital Responsive and Resistant Idiopathic Epileptic Border Collies

Alves

Hülsmeyer

Jaggy

et al. 2011

Veterinary Internal Medicne

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Background: Variation in the ABCB1 gene is believed to play a role in drug resistance in epilepsy. Hypothesis/Objectives: Variation in the ABCB1 gene encoding the permeability-glycoprotein could have an influence on phenobarbital (PB) resistance, which occurs with high frequency in idiopathic epileptic Border Collies (BCs).Animals: Two hundred and thirty-six client-owned BCs from Switzerland and Germany including 25 with idiopathic epilepsy, of which 13 were resistant to PB treatment.Methods: Prospective and retrospective case-control study. Data were collected retrospectively regarding disease status, antiepileptic drug (AED) therapy, and drug responsiveness. The frequency of a known mutation in the ABCB1 gene (4 base-pair deletion in the ABCB1 gene [c.296_299del]) was determined in all BCs. Additionally, the ABCB1 coding exons and flanking sequences were completely sequenced to search for additional variation in 41 BCs. Association analyses were performed in 2 case-control studies: idiopathic epileptic and control BCs and PB-responsive and resistant idiopathic epileptic BCs.Results: One of 236 BCs (0.4%) was heterozygous for the mutation in the ABCB1 gene (c.296_299del). A total of 23 variations were identified in the ABCB1 gene: 4 in exons and 19 in introns. The G-allele of the c.-6-180T 4 G variation in intron 1 was significantly more frequent in epileptic BCs resistant to PB treatment than in epileptic BCs responsive to PB treatment (P raw 5 .0025).Conclusions and Clinical Importance: A variation in intron 1 of the ABCB1 gene is associated with drug responsiveness in BCs. This might indicate that regulatory mutations affecting the expression level of ABCB1 could exist, which may influence the reaction of a dog to AEDs.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Polymorphisms in the ABCB1 Gene in Phenobarbital Responsive and Resistant Idiopathic Epileptic Border Collies

Alves

Hülsmeyer

Jaggy

et al. 2011

Veterinary Internal Medicne

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“…Recently, the greater activity of the S581 allele was confirmed on transepithelial transport of antibiotics using stably transduced cell models (Real et al, 2011a). The present study compares plasma and milk pharmacokinetics in Y/S 581 heterozygous and Y/Y 581 homozygous lactating cows that received danofloxacin, a widely used antibiotic for the treatment of infections of the respiratory tract, intestinal tract, and mammary glands (Poutrel et 2008; Schrickx and Fink-Gremmels, 2008). The aim of our study is to show, for the first time, the potential in vivo applicability of our previous in vitro results relative to the effect of Y581S SNP on drug secretion into milk in livestock.…”

Section: Introductionmentioning

confidence: 99%

The Bovine ATP-Binding Cassette Transporter ABCG2 Tyr581Ser Single-Nucleotide Polymorphism Increases Milk Secretion of the Fluoroquinolone Danofloxacin

et al. 2012

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The bovine adenosine triphosphate-binding cassette transporter G2 (ABCG2/breast cancer resistance protein) polymorphism Tyr581Ser (Y581S) has recently been shown to increase in vitro transepithelial transport of antibiotics. Since this transporter has been extensively related to the active secretion of drugs into milk, the potential in vivo effect of this polymorphism on secretion of xenobiotics in livestock could have striking consequences for milk production, the dairy industry, and public health. Our purpose was to study the in vivo effect of this polymorphism on the secretion of danofloxacin, a widely used veterinary antibiotic, into milk. Danofloxacin (1.25 mg/kg) was administered to six Y/Y 581 homozygous and six Y/S 581 heterozygous lactating cows, and plasma and milk samples were collected and analyzed by high-performance liquid chromatography. No differences were found in the pharmacokinetic parameters of danofloxacin in plasma between the two groups of animals. In contrast, Y/S heterozygous cows showed a 2-fold increase in danofloxacin levels in milk. In addition, the pharmacokinetic elimination parameters, mean residence time and elimination half-life, were significantly lower in the milk of the animals carrying the Y/S polymorphism. These in vivo results are in agreement with our previously published in vitro data, which showed a greater capacity of the S581 variant in accumulation assays, and demonstrate, for the first time, an important effect of the Y581S single-nucleotide polymorphism on antibiotic secretion into cow milk. These findings could be extended to other ABCG2 substrates, and may be relevant for the treatment of mastitis and for the design of accurate and novel strategies to handle milk residues. IntroductionThe ATP-binding cassette (ABC) transporter ABCG2 (breast cancer resistance protein) is expressed in a wide range of tissues and organs, including the intestine, liver, blood-brain barrier, and mammary gland (van Herwaarden and Schinkel, 2006). It affects the bioavailability of its substrates and mediates the active secretion of xenobiotics and several vitamins in milk (van Herwaarden et al., 2007). The occurrence of drug residues in milk could lead to the development of bacterial resistance, allergies, or hypersensitivity reactions in consumers (McManaman and Neville, 2003). On the other hand, effective treatments for mastitis may require a considerable transfer of drugs into milk (Escudero et al., 2007). All of these issues are of great concern for general public health, the dairy industry, and veterinary therapeutics. Hence, identification of relevant factors for the transfer of drugs into milk in livestock constitutes a priority.Changes in the expression and/or the function of ABCG2 can lead to dramatic variations in the pharmacokinetics and secretion of its substrates into milk Ni et al., 2010). Several single-nucleotide polymorphisms (SNPs) have been studied in human ABCG2, and of these, Gln141Lys (Q141K) is one of the most important, causing impaired urate transport wh...

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“…Due to its location in the apical or brush border membrane of enterocytes, MDR1 can have a great impact on the bioavailability of certain drugs [35,[83][84][85]. Consequently, MDR1…”

Section: Mdr1 (Abcb1)mentioning

confidence: 99%

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

Stieger

Meier

2011

Pharmacogenomics

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This article summarizes the impact of the pharmacogenetics of drug transporters expressed in the enterohepatic circulation on the pharmacokinetics and pharmacodynamics of drugs. The role of pharmacogenetics in the function of drug transporter proteins in vitro is now well established and evidence is rapidly accumulating from in vivo pharmacokinetic studies, which suggests that genetic variants of drug transporter proteins can translate into clinically relevant phenotypes. However, a large amount of conflicting information on the clinical relevance of drug transporter proteins has so far precluded the emergence of a clear picture regarding the role of drug transporter pharmacogenetics in medical practice. This is very well exemplified by the case of P-glycoprotein (MDR1, ABCB1). The challenge is now to develop pharmacogenetic models with sufficient predictive power to allow for translation into drug therapy. This will require a combination of pharmacogenetics of drug transporters, drug metabolism and pharmacodynamics of the respective drugs.

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Implications of ABC transporters on the disposition of typical veterinary medicinal products

Cited by 63 publications

References 144 publications

Polymorphisms in the ABCB1 Gene in Phenobarbital Responsive and Resistant Idiopathic Epileptic Border Collies

Polymorphisms in the ABCB1 Gene in Phenobarbital Responsive and Resistant Idiopathic Epileptic Border Collies

The Bovine ATP-Binding Cassette Transporter ABCG2 Tyr581Ser Single-Nucleotide Polymorphism Increases Milk Secretion of the Fluoroquinolone Danofloxacin

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

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