Role of ABC Transporters in Veterinary Drug Research and Parasite Resistance

Alvarez, Ana I.; Merino, Gracia; Molina, A.; Pulido, Mivis M.; McKellar, Quintin; Prieto, J. E.

doi:10.2174/156720106776359195

Cited by 33 publications

(20 citation statements)

References 90 publications

(153 reference statements)

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“…In contrast, milk‐to‐plasma concentrations ratio of OFZ was approximately 1 for the whole sampling period. The milk‐to‐plasma ratio may allow the prediction of potential active BCRP‐mediated drug secretion and, in consequence, residual accumulation of BCRP substrates into milk (Alvarez et al., ). Therefore, the current data corroborate results recently obtained by in vitro BCRP flux studies (Mahnke et al., ) showing active BCRP‐mediated secretion of MNPSO 2 .…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic assessment of the monepantel plus oxfendazole combined administration in dairy cows

Ballent

Viviani

Imperiale

et al. 2017

Vet Pharm & Therapeutics

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Monepantel (MNP) is a novel anthelmintic compound launched into the veterinary pharmaceutical market. MNP is not licenced for use in dairy animals due to the prolonged elimination of its metabolite monepantel sulphone (MNPSO ) into milk. The goal of this study was to evaluate the presence of potential in vivo drug-drug interactions affecting the pattern of milk excretion after the coadministration of the anthelmintics MNP and oxfendazole (OFZ) to lactating dairy cows. The concentrations of both parent drugs and their metabolites were measured in plasma and milk samples by HPLC. MNPSO was the main metabolite recovered from plasma and milk after oral administration of MNP. A high distribution of MNPSO into milk was observed. The milk-to-plasma ratio (M/P ratio) for this metabolite was equal to 6.75. Conversely, the M/P ratio of OFZ was 1.26. Plasma concentration profiles of MNP and MNPSO were not modified in the presence of OFZ. The pattern of MNPSO excretion into milk was also unchanged in animals receiving MNP plus OFZ. The percentage of the total administered dose recovered from milk was 0.09 ± 0.04% (MNP) and 2.79 ± 1.54% (MNPSO ) after the administration of MNP alone and 0.06 ± 0.04% (MNP) and 2.34 ± 1.38% (MNPSO ) after the combined treatment. The presence of MNP did not alter the plasma and milk disposition kinetics of OFZ. The concentrations of the metabolite fenbendazole sulphone tended to be slightly higher in the coadministered group. Although from a pharmacodynamic point of view the coadministration of MNP and OFZ may be a useful tool, the presence of OFZ did not modify the in vivo pharmacokinetic behaviour of MNP and therefore did not result in reduced milk concentrations of MNPSO .

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic assessment of the monepantel plus oxfendazole combined administration in dairy cows

Ballent

Viviani

Imperiale

et al. 2017

Vet Pharm & Therapeutics

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“…Binding of xenobiotics to these integral membrane proteins is followed by ATP binding and conformational changes that cause export of compounds; ATP hydrolysis allows regeneration of the initial state of the protein (Schinkel and Jonker 2003). Comprehensive information on xenobiotic transporter diversity and function is well reviewed (Kerboeuf et al 2003; Sheps et al 2004; Alvarez et al 2006; Lindblom and Dodd 2006). ABC transporters have a well established role in promoting chemotherapeutic resistance in some cancer cells and have been an important target for reversing resistance in humans (Kerboeuf et al 2003).…”

Section: Xenobiotic Detoxification Promotes Multidrug Resistancementioning

confidence: 99%

“…ABC transporters have a well established role in promoting chemotherapeutic resistance in some cancer cells and have been an important target for reversing resistance in humans (Kerboeuf et al 2003). As a result, this phase of detoxification has received the most attention in parasites (Alvarez et al 2006; Lespine et al 2008). …”

Section: Xenobiotic Detoxification Promotes Multidrug Resistancementioning

confidence: 99%

Unique structure and regulation of the nematode detoxification gene regulator, SKN-1: implications to understanding and controlling drug resistance

Choe¹,

Leung²,

Miyamoto³

2012

Drug Metabolism Reviews

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Nematodes parasitize an alarming number of people and agricultural animals globally and cause debilitating morbidity and mortality. Anthelmintics have been the primary tools used to control parasitic nematodes for the past several decades, but drug resistance is becoming a major obstacle. Xenobiotic detoxification pathways defend against drugs and other foreign chemicals in diverse organisms, and evidence is accumulating that they play a role in mediating resistance to anthelmintics in nematodes. Related anti-oxidation pathways may also provide filarial parasites protection against host free radical-mediated immune responses. Upstream regulatory pathways have received almost no attention in nematode parasites despite their potential to co-regulate multiple detoxification and anti-oxidation genes. The NRF2 transcription factor mediates inducible detoxification and anti-oxidation defenses in mammals and recent studies have demonstrated that it promotes multidrug resistance in some human tumors. Recent studies in the free-living model nematode Caenorhabditis elegans have defined the homologous transcription factor SKN-1 as a master regulator of detoxification and anti-oxidation genes. Despite similar functions, SKN-1 and NRF2 have important differences in structure and regulatory pathways. Protein alignment and phylogenetic analyses indicate that these differences are shared among many nematodes making SKN-1 a candidate for specifically targeting nematode detoxification and anti-oxidation.

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“…Since it has a broad specificity and is partial to organic amphipathic molecules, the normal physiological role of P-gp is thought to be a defence mechanism against harmful xenobiotics. Hence, efflux by Pgp is one of the mechanisms that resistant cancer cells use to avoid many chemotherapeutics (reviewed in Alvarez et al 2006). In addition, inhibitors and inducers of P-gp at the BBB are thought to have potential to produce veterinary drug-drug interactions (Mealey 2004).…”

Section: Introductionmentioning

confidence: 99%

Avermectin transepithelial transport in MDR1- and MRP-transfected canine kidney monolayers

Brayden

Griffin

2007

Vet Res Commun

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Fluxes of the anti-parasitic agents, [(3)H]-ivermectin, [(3)H]-selamectin and [(3)H]-moxidectin were studied across non-transfected and transfected canine kidney epithelial monolayers, MDCK II/wt, MDCK II-MDR1, MDCK II-MRP1 and MDCK II-MRP2. All four lines surprisingly expressed significant levels of P-glycoprotein (P-gp), coded for by MDR1, but MDCK II-MDR1 expressed increased levels compared to the other lines. MDCK II-MRP1 and MDCK II-MRP2 expressed increased levels of MRP1 and MRP2 respectively. Fluxes of [(3)H]-ivermectin, [(3)H]-selamectin, [(3)H]-moxidectin, and the P-gp substrates, rhodamine-123 and DiOC(2), were polarized in the basolateral-to-apical (secretory) direction across the four lines. Selected MRP inhibitors used in relevant pharmacological concentrations did not block the secretory fluxes of either [(3)H]-ivermectin or [(3)H]-selamectin in either the non-transfected or MRP-transfected lines. In contrast, secretory fluxes of ivermectin and selamectin were inhibited in all four lines by the P-gp inhibitor, verapamil. These data confirm that ivermectin and selamectin are substrates for P-gp in four additional cell lines, but suggest that they are not significant substrates for MRP1 or MRP2 where there is background expression of P-gp. Since this pattern of expression also pertains on the blood-brain barrier, it is unlikely that MRP1 and MRP2 play a significant role in ivermectin and selamectin blood: brain distribution in vivo.

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Role of ABC Transporters in Veterinary Drug Research and Parasite Resistance

Cited by 33 publications

References 90 publications

Pharmacokinetic assessment of the monepantel plus oxfendazole combined administration in dairy cows

Pharmacokinetic assessment of the monepantel plus oxfendazole combined administration in dairy cows

Unique structure and regulation of the nematode detoxification gene regulator, SKN-1: implications to understanding and controlling drug resistance

Avermectin transepithelial transport in MDR1- and MRP-transfected canine kidney monolayers

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