22 research outputs found
Secretion into Milk of the Main Metabolites of the Anthelmintic Albendazole Is Mediated by the ABCG2/BCRP Transporter
Albendazole (ABZ) is an anthelmintic with a broad-spectrum activity, widely used in human and veterinary medicine. ABZ is metabolized in all mammalian species to albendazole sulfoxide (ABZSO), albendazole sulfone (ABZSO2) and albendazole 2-aminosulphone (ABZSO2-NH2). ABZSO and ABZSO2 are the main metabolites detected in plasma and all three are detected in milk. The ATP-binding cassette transporter G2 (ABCG2) is an efflux transporter that is involved in the active secretion of several compounds into milk. Previous studies have reported that ABZSO was in vitro transported by ABCG2. The aim of this work is to correlate the in vitro interaction between ABCG2 and the other ABZ metabolites with their secretion into milk by this transporter. Using in vitro transepithelial assays with cells transduced with murine Abcg2 and human ABCG2, we show that ABZSO2 and ABZSO2-NH2 are in vitro substrates of both. In vivo assays carried out with wild-type and Abcg2−/− lactating female mice demonstrated that secretion into milk of these ABZ metabolites was mediated by Abcg2. Milk concentrations and milk-to-plasma ratio were higher in wild-type compared to Abcg2−/− mice for all the metabolites tested. We conclude that ABZ metabolites are undoubtedly in vitro substrates of ABCG2 and actively secreted into milk by ABCG2.S
In vitro interaction of the pesticides flupyradifurone, bupirimate and its metabolite ethirimol with the ATP-binding cassette transporter G2 (ABCG2)
[EN] ABCG2 is an ATP-binding cassette efflux transporter that is expressed in absorptive and excretory organs such as liver, intestine, kidney, brain and testis where it plays a crucial physiological and toxicological role in protecting cells against xenobiotics, affecting pharmacokinetics of its substrates. In addition, the induction of ABCG2 expression in mammary gland during lactation is related to active secretion of many toxicants into milk. In this study, the in vitro interactions between ABCG2 and three pesticides flupyradifurone, bupirimate and its metabolite ethirimol were investigated to check whether these compounds are substrates and/or inhibitors of this transporter. Using in vitro transepithelial assays with cells transduced with murine, ovine and human ABCG2, we showed that ethirimol and flupyradifurone were transported efficiently by murine Abcg2 and ovine ABCG2 but not by human ABCG2. Bupirimate was not found to be an in vitro substrate of ABCG2 transporter. Accumulation assays using mitoxantrone in transduced MDCK-II cells suggest that none of the tested pesticides were efficient ABCG2 inhibitors, at least in our experimental conditions. Our studies disclose that ethirimol and flupyradifurone are in vitro substrates of murine and ovine ABCG2, opening the possibility of a potential relevance of ABCG2 in the toxicokinetics of these pesticides.S
Transporters in the Mammary Gland—Contribution to Presence of Nutrients and Drugs into Milk
[EN] A large number of nutrients and bioactive ingredients found in milk play an important role in the nourishment of breast-fed infants and dairy consumers. Some of these ingredients include physiologically relevant compounds such as vitamins, peptides, neuroactive compounds and hormones. Conversely, milk may contain substances—drugs, pesticides, carcinogens, environmental pollutants—which have undesirable effects on health. The transfer of these compounds into milk is unavoidably linked to the function of transport proteins. Expression of transporters belonging to the ATP-binding cassette (ABC-) and Solute Carrier (SLC-) superfamilies varies with the lactation stages of the mammary gland. In particular, Organic Anion Transporting Polypeptides 1A2 (OATP1A2) and 2B1 (OATP2B1), Organic Cation Transporter 1 (OCT1), Novel Organic Cation Transporter 1 (OCTN1), Concentrative Nucleoside Transporters 1, 2 and 3 (CNT1, CNT2 and CNT3), Peptide Transporter 2 (PEPT2), Sodium-dependent Vitamin C Transporter 2 (SVCT2), Multidrug Resistance-associated Protein 5 (ABCC5) and Breast Cancer Resistance Protein (ABCG2) are highly induced during lactation. This review will focus on these transporters overexpressed during lactation and their role in the transfer of products into the milk, including both beneficial and harmful compounds. Furthermore, additional factors, such as regulation, polymorphisms or drug-drug interactions will be described.S
Ivermectin reduces secretion of meloxicam into milk by inhibition of ABCG2 transporter in sheep
[EN] The ATP-binding cassette transporter G2 (ABCG2) is an efflux protein involved
in the bioavailability and secretion into milk of several compounds including anti-
inflammatory drugs. The aim of this work was to determine the effect in sheep of an
ABCG2 inhibitor, such as the macrocyclic lactone ivermectin, on the secretion into milk
of meloxicam, a non-steroidal anti-inflammatory drug widely used in veterinary
medicine, and recently reported as an ABCG2 substrate in mice. In vitro meloxicam
transport assays in ovine ABCG2-transduced cells have shown that meloxicam is a
substrate of ovine ABCG2 and that ivermectin is an efficient inhibitor of in vitro transport
of meloxicam mediated by ovine ABCG2. In addition, the role of ovine ABCG2 in
secretion into milk of meloxicam was corroborated using Assaf lactating sheep
coadministered with ivermectin. Animals were administered subcutaneously with
meloxicam (0.5 mg/kg) with or without ivermectin (0.2 mg/kg). A significantly lower
concentration of meloxicam in milk was detected when ivermectin was coadministered,
revealing a major role of ABCG2 in the secretion into milk of meloxicam and a relevant
drug-drug interaction affecting this process. These results will contribute to the
understanding of the potential factors that modulate the transfer of anti-inflammatory
drugs into milk, opening their potential use in lactating ruminants, and the effect of drug
coadministration on the presence of milk residues of these compounds.S
The ABCG2 protein in vitro transports the xenobiotic thiabendazole and increases the appearance of its residues in milk
[EN] Thiabendazole (2–(4–thiazolyl)benzimidazole, TBZ) is a broad–spectrum anthelmintic widely used in humans and cattle. It is also used as post–harvest agricultural fungicide, thus preserving crop quality and marketability (Hajikhani et al., 2024). Adverse effects after TBZ exposure including endocrine, nephrogenic, hepatogenic, teratogenic and neurological effects have been reported in mammals (Ekman et al., 2014). Etiological factors behind TBZ toxicity remain ambiguous; however, it has been hypothesized that it may be due to its bioactivation to 5OH–TBZ by the cytochrome P450 1A2 (CYP1A2) (Coulet et al., 1998a; Jamieson et al., 2011) (Fig. 1). Therefore, National and International Food Safety Authorities have established regulations for the usage of TBZ on food products setting maximum residue limits (MRLs) for the sum of TBZ and its metabolites in both agricultural and animal products ranging from 0.01 to 7 mg/kg depending on the product (European Food Safety Authority (EFSA) et al., 2021; U.S. Food and Drug Administration (FDA), 2021). Unfortunately, MRLs derived from pesticide use are equal to or higher than veterinary MRLs for all commodities, and the possible aggregated exposure from TBZ residues has not been studied, making it impossible to rule out an overexposure to TBZ through the food chain.SIPublicación en abierto financiada por el Consorcio de Bibliotecas Universitarias de Castilla y León (BUCLE), con cargo al Programa Operativo 2014ES16RFOP009 FEDER 2014-2020 DE CASTILLA Y LEÓN, Actuación:20007-CL - Apoyo Consorcio BUCL
Coadministration of ivermectin and abamectin affects milk pharmacokinetics of the antiparasitic clorsulon in Assaf sheep
[EN] In veterinary field, drug exposure during milk production in dairy cattle is considered
a major health problem which concerns dairy consumers. The induced expression
of the ABC transporter G2 (ABCG2) in the mammary gland during lactation plays
a significant role in the active secretion of many compounds into milk. The
main objective of this study was to determine the involvement of ABCG2 in the
secretion into milk of the antiparasitic clorsulon in sheep as well as the possible
effect of the coadministration of model ABCG2 inhibitors such as macrocyclic
lactones on this process. Cells transduced with the ovine variant of ABCG2 were
used to carry out in vitro transepithelial transport assays in which we showed
that clorsulon is a substrate of the ovine transporter. In addition, ivermectin and
abamectin significantly inhibited clorsulon transport mediated by ovine ABCG2. In
vivo interactions were studied in Assaf sheep after coadministration of clorsulon
(in DMSO, 2 mg/kg, s.c.) with ivermectin (Ivomec®, 0.2 mg/kg, s.c.) or abamectin
(in DMSO, 0.2 mg/kg, s.c.). After ivermectin and abamectin treatment, no relevant
statistically significant differences in plasma levels of clorsulon were reported
between the experimental groups since there were no differences in the area
under the plasma concentration-curve (AUC) between clorsulon treatment alone
and coadministration with macrocyclic lactones. With regard to milk, total amount
of clorsulon, as percentage of dose excreted, did not show statistically significant
differences when macrocyclic lactones were coadministered. However, the
AUC for clorsulon significantly decreased (p < 0.05) after coadministration with
ivermectin (15.15 ± 3.17 μg h/mL) and abamectin (15.30 ± 3.25 μg h/mL) compared
to control group (20.73 ± 4.97 μg h/mL). Moreover, milk parameters such as half-
life (T1/2) and mean residence time (MRT) were significantly lower (p < 0.05) after
coadministration of macrocyclic lactones. This research shows that the milk
pharmacokinetics of clorsulon is affected by the coadministration of ABCG2
inhibitors, reducing drug persistence in milk.S
Role of the Abcg2 Transporter in Secretion into Milk of the Anthelmintic Clorsulon: Interaction with Ivermectin
[EN] Clorsulon is a benzenesulfonamide drug that is effective in treating helminthic zoonoses such as fascioliasis. When used in combination with the macrocyclic lactone
ivermectin, it provides high broad-spectrum antiparasitic efficacy. The safety and efficacy
of clorsulon should be studied by considering several factors such as drug-drug interactions mediated by ATP-binding cassette (ABC) transporters due to their potential effects
on the pharmacokinetics and drug secretion into milk. The aim of this work was to determine the role of ABC transporter G2 (ABCG2) in clorsulon secretion into milk and the
effect of ivermectin, a known ABCG2 inhibitor, on this process. Using in vitro transepithelial assays with cells transduced with murine Abcg2 and human ABCG2, we report that
clorsulon was transported in vitro by both transporter variants and that ivermectin inhibited its transport mediated by murine Abcg2 and human ABCG2. Wild-type and Abcg22/2
lactating female mice were used to carry out in vivo assays. The milk concentration and
the milk-to-plasma ratio were higher in wild-type mice than in Abcg22/2 mice after clorsulon administration, showing that clorsulon is actively secreted into milk by Abcg2. The
interaction of ivermectin in this process was shown after the coadministration of clorsulon
and ivermectin to wild-type and Abcg22/2 lactating female mice. Treatment with ivermectin had no effect on the plasma concentrations of clorsulon, but the milk concentrations
and milk-to-plasma ratios of clorsulon decreased in comparison to those with treatment
without ivermectin, only in wild-type animals. Consequently, the coadministration of clorsulon and ivermectin reduces clorsulon secretion into milk due to drug-drug interactions
mediated by ABCG2S
Role of ABCG2 in secretion into milk of the anti-inflammatory flunixin and its main metabolite: in vitro-in vivo correlation in mice and cows
35 p.Flunixin meglumine is a nonsteroidal anti-inflammatory drug (NSAID) widely used in
veterinary medicine. It is indicated to treat inflammatory processes, pain and pyrexia in farm
animals. In addition, it is one of the few NSAIDs approved for use in dairy cows, and
consequently gives rise to concern regarding its milk residues. The ABCG2 efflux transporter is
induced during lactation in the mammary gland and plays an important role in the secretion of
different compounds into milk. Previous reports have demonstrated that bovine ABCG2 Y581S
polymorphism increases fluoroquinolone levels in cow milk. However, the implication of this
transporter in the secretion into milk of anti-inflammatory drugs has not yet been studied. The
objective of this work was to study the role of ABCG2 in the secretion into milk of flunixin and
its main metabolite, 5-hydroxyflunixin, using Abcg2(-/-) mice, and to investigate the implication
of the Y581S polymorphism in the secretion of these compounds into cow milk. Correlation
with the in vitro situation was assessed by in vitro transport assays using MDCKII cells
overexpressing murine and the two variants of the bovine transporter. Our results show that
flunixin and 5-hydroxyflunixin are transported by ABCG2 and that this protein is responsible
for their secretion into milk. Moreover, the Y581S polymorphism increases flunixin
concentration into cow milk, but it does not affect milk secretion of 5-hydroxyflunixin. This
result correlates with the differences in the in vitro transport of flunixin between the two bovine
variants. These findings are relevant to the therapeutics of anti-inflammatory drug
Abcg2 transporter affects plasma, milk and tissue levels of meloxicam
33 p.ATP-binding cassette (ABCG2) is an efflux transporter that extrudes xenotoxins from cells in liver, intestine, mammary gland, brain and other organs, affecting the pharmacokinetics, brain accumulation and secretion into milk of several compounds, including antitumoral, antimicrobial and anti-inflammatory drugs. The aim of this study was to investigate whether the widely used anti-inflammatory drug meloxicam is an Abcg2 sustrate, and how this transporter affects its systemic distribution. Using polarized ABCG2-transduced cell lines, we found that meloxicam is efficiently transported by murine Abcg2 and human ABCG2. After oral administration of meloxicam, the area under the plasma concentration-time curve in Abcg2-/- mice was 2-fold higher than in wild type mice (146.06 ± 10.57 μg·h/ml versus 73.80 ± 10.00 μg·h/ml). Differences in meloxicam distribution were reported for several tissues, with a 20-fold higher concentration in the brain of Abcg2-/- compared to wild-type mice. Meloxicam secretion into milk was also affected by the transporter, with a 2.5-fold higher milk-to-plasma ratio in wild-type compared with Abcg2-/- lactating female mice (0.58 ± 0.08 versus 0.23 ± 0.06). We conclude that Abcg2 is an important determinant of the plasma and brain distribution of meloxicam and is clearly involved in its secretion into milk.
This study was supported by the research projects AGL2015-65626-R (MINECO/FEDER, UE) and RTI2018-100903-B-I00 (AEI/FEDER, UE); and by the predoctoral grants from the Ministry of Economy, Industry and Competitiveness (BES-2016-077235 grant to AMGL), and from Spanish Ministry of Education, Culture and Sport (FPU14/05131 grant to DGM AND FPU18/01559 grant to EBP); and the Junta de Castilla y Leon and European Regional Development Fund (Post-Doctoral Fellowship LE011P17 grant to IAF)
Abcg2 transporter affects plasma, milk and tissue levels of meloxicam
https://doi.org/10.1016/j.bcp.2020.113924ATP-binding cassette (ABCG2) is an efflux transporter that extrudes xenotoxins from cells in liver, intestine, mammary gland, brain and other organs, affecting the pharmacokinetics, brain accumulation and
secretion into milk of several compounds, including antitumoral, antimicrobial and anti-inflammatory drugs. The aim of this study was to investigate whether the widely used anti-inflammatory drug meloxicam is
an Abcg2 sustrate, and how this transporter affects its systemic distribution. Using polarized ABCG2-transduced cell lines, we found that meloxicam is efficiently transported by murine Abcg2 and human ABCG2. After oral administration of meloxicam, the area under the plasma concentration-time curve in Abcg2-/- mice was 2-fold higher than in wild type mice (146.06 ± 10.57 μg·h/ml versus 73.80 ± 10.00 μg·h/ml). Differences in meloxicam distribution were reported for several tissues after oral and intravenous administration, with a 20-fold higher concentration in the brain of Abcg2-/- after oral administration.
Meloxicam secretion into milk was also affected by the transporter, with a 2-fold higher milk-to-plasma ratio in wild-type compared with Abcg2-/- lactating female mice after oral and intravenous administration. We conclude that Abcg2 is an important determinant of the plasma and brain distribution of meloxicam and is clearly involved in its secretion into milk.S