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Rev. Bras. Saúde Prod. Anim., Salvador, v.20, 1 -12, e0112019, 2019 ISSN 1519 9940
http://dx.doi.org/10.1590/S1519-994020 01012019
Ivermectin and albendazole withdrawal period in goat milk
Período de carência de ivermectina e albendazol em leite de cabras
Santos, Patrícia Silva1; Cruz, Jurandir Ferreira da2; Santos, José Soares dos3 ; Mottin, Vanessa Daniele2 ;
Teixeira Neto, Milton Rezende4; Souza, Jennifer Figueredo2
1. Instituto Federal da Bahia, Itapetinga – BA, Brasil. E-mail: patizootecnia@gmail.com
2. Universidade Estadual do Sudoeste da Bahia, Laboratório de Reprodução de Caprinos e
Ovinos, Departamento de Fitotecnia e Zootecnia, Vitória da Conquista – BA, Brasil. E-mail:
cruzjurandir@gmail.com, vmottin@yahoo.com.br, laurela4@hotmail.com
3. Universidade Estadual do Sudoeste da Bahia, Laboratório de Química Analítica,
Departamento de química, Vitória da Conquista – BA, Brasil. E-mail: zesoares@uesb.edu.br
4. Faculdade de Tecnologia e Ciências, Curso de Medicina Veterinária, Vitória da Conquista –
BA, Brasil. E-mail: rezendeteixeira@yahoo.com.br
SUMMARY albendazole or ivermectin does not contain
its respective residues in detectable
amounts from the 4th and 42nddays,
respectively, after antiparasitic treatment.
Theaimthis study was to determine the
excretion profile of albendazole and keywords: HPLC, goat milk, residues.
ivermectin residues in milk from goats
submitted to antiparasitic treatment.
Twenty-four Brazilianmongrel lactating and RESUMO
pluriparous goats, maintained extensively
on native pasture were orally treatedwith Objetivou-se determinar o perfil de
albendazole or ivermectin. Milk samples excreção de resíduos de albendazole e
were collected before and after vermifuges ivermectina em leite de cabras submetidas a
application, in the days 0, 2, 3 e 4 to tratamento antiparasitário. Vinte e quatro
albendazole and 0, 3, 7, 14, 21, 28, 35 and cabras sem padrão racial definido (SPRD),
42 to ivermectin. The vermifuges residues lactantes, pluríparas, criadas
were detected by high performance liquid extensivamente em pastagem nativa foram
cromatography with ultravioletdetector. The tratadas com albendazole ou ivermectina,
amount of residues contained in themilk via oral. As amostras de leite foram
was decreasing in function of time. The coletadas antes e após a aplicação dos
mean daily rates of decrease of albendazole vermífugos, nos dias 0, 1, 2, 3 e 4 para
residues were 63.34%, 40.18 and 100.0%, Albendazole e 0, 3, 7, 14, 21, 28, 35 e 42
from the 2ndto the 4thday, respectively; on para ivermectina. Os resíduos dos
the 3rdday after treatment, 50% of the vermífugos foram determinados por meio
samples showed concentrations ≥ 47.61 de cromatografia líquida de alta eficiência
µg.mL-1, and on the 4thday, no sample had com detector ultravioleta. A quantidade de
albendazole residue.The amount excreted of resíduos presentes no leite foi decrescente
ivermectin was similar between the 3rdand em função do tempo. As taxas medias
21stday when all samples presented values ≥ diárias de decréscimo dos resíduos de
51.90 µg.mL-1; on the 35th day, 50% of the albendazole foram 63,34%, 40,18 e
samples showed values above of 100,0%, do 2º ao 4º dia, respectivamente;
recommended levels, and on the 42nd day, no 3º dia após o tratamento, 50% das
no sample had detectable ivermectin amostras apresentaram concentrações ≥
residue.In conclusion, the milk of Brazilian 47,61 µg.mL-1 e no 4º dia, nenhuma
mongrel goats treated orally with amostra apresentou resíduo de albendazole.
Received on: 09/08/2018. Accepted on: 07/12/2018
1Rev. Bras. Saúde Prod. Anim., Salvador, v.20, 1 -12, e0112019, 2019 ISSN 1519 9940
http://dx.doi.org/10.1590/S1519-994020 01012019
Os teores excretados de ivermectina foram
similares entre o 3º e 21º dia, quando todas
as amostras apresentaram valores ≥ 51,90
µg.mL-1; no 35º dia, 50% das amostras
apresentavam valores acima nos níveis
recomendáveis; no 42º dia, nenhuma
amostra apresentou resíduo detectável de
ivermectina. Conclui-se que o leite de
cabras SPRD tratadas oralmente com
albendazole ou ivermectina não apresenta
seus respectivos resíduos em quantidades
detectáveis a partir do 4º e 42º dias,
respectivamente, após tratamento
antiparasitário.
Palavras chave: CLAE, leite caprino,
resíduos.
Received on: 09/08/2018. Accepted on: 07/12/2018
2Rev. Bras. Saúde Prod. Anim., Salvador, v.20, 1 -12, e0112019, 2019 ISSN 1519 9940
http://dx.doi.org/10.1590/S1519-994020 01012019
INTRODUCTION mammalian species (Ema, 2004). The
Codex Alimentarius established the
In developing countries, the use of goat maximum residue limit of ivermectin in
milk has become a useful strategy to milk at 10 µg L-1 (Fao/Who, 1993).
combat malnutrition, considering that Considering that information about
its high nutritional value contributes excretion of antiparasitic drugs through
with a significant part of the goat milk is scarce and that goat milk is
consumption of protein by the low- a food commonly used to human
income population (Haenlein, 2004; consumption, this study aimed to
Park et al., 2007). In the semi-arid determine the excretion profile of
region of Brazil, goat milk performs an albendazole and ivermectin residues in
important social role, being common its goat milk submitted to antiparasitic
use as food by many rural families treatment.
(Ribeiro & Ribeiro, 2001).
Although the milk production destined
to consumption should avoid to the MATERIALS AND METHODS
maximum the presence of
pharmacological residues that cause
risks to human health (Anvisa, 2006), Animals and colleting samples
thedrugs administration aimed to
endoparasites control in dairy herds is a This study was approved by the Ethics
frequent practice in Brazil. Committee on the Use of Animals of
Benzimidazoles residues (Brandon et the State University of Southwest of
al., 2002) and ivermectin residues Bahia, with protocol nº. 162/2018.
(Turnipseed et al., 2005; Souza et al., Twenty-four Brazilian mongrel
2007) were detected in bovine milk lactating and pluriparous goats were
destined tohuman consumption. used in this study, of which 12 were
Due to the low cost and the possibility dewormed with albendazole (Aldazol
of use in lactating females, Oral®, Vallée, Brazil) at a dose of 7.5
benzimidazoles have been the most mg kg-1 of body weight and others 12
used antiparasitic drugs in the last goats were dewormed with ivermectin
decades (Dayan, 2003). Fao/Who (Ivomec Oral®, Merial, Brazil) at a
(1989), alert to the toxic effect of dose of 200 µg / kg body weight, as
albendazole, including some studies suggested by the manufacturers.
about carcinogenic, genotoxic and The milk samples were collected before
teratogenic effects (Lanusse et al., and after vermifuges application in the
2009); the European Community and days D0, D1, D2, D3, and D4 to
Anvisa established the maximum Albendazole and D0, D3, D7, D14, D21,
residue limit of albendazole in milk at D28, D35 and D42 to ivermectin. D0 was
100µg L-1 (EC, 2004; Anvisa, 2012). the day of vermifuges application.The
Although ivermectin has a high safety days and the collecting period were
margin in antiparasitic treatments defined according to the time of drug
(Ayres & Almeida, 2002), some of its metabolism, described in previous
excretion occurs through the mammary studies, and according to the withdrawal
gland (Flajs et al., 2005). Although period established by the
these effects have not been evidenced in manufacturers.The samples were
pregnant women (Chippaux et al., conditioned in disposable plastic bags
1993), the presence of ivermectin identified and kept frozen in the freezer
residues in milk may have mutagenic (-20oC) until the moment of analysis at
and/or teratogenic effects in some Laboratory of Analytical Chemistry of
Received on: 09/08/2018. Accepted on: 07/12/2018
3Rev. Bras. Saúde Prod. Anim., Salvador, v.20, 1 -12, e0112019, 2019 ISSN 1519 9940
http://dx.doi.org/10.1590/S1519-994020 01012019
UESB to determine the administered activation of extraction cartridges in
vermifuges residues. solid phase – silica-C18 19% carbon
(500 mg.3 mL-1), ii) adsorption of
Chromatographic analysis albendazole or ivermectin to the
sorbent, iii) albendazole or ivermectin
The reference analytical solutions were elution, and iv) cartridge washing.
prepared by successive dilutions of For the cartridge activation were used 3
albendazole standard (Albendazole®, mL of acetone and 2 mL of acetonitrile
Fluka, Sigma-Aldrich, USA) and with vacuum application to reach a flow
ivermectin standard (Ivermectin®, of 3 mL.min-1. Posteriorly, for
Sigma-Aldrich, USA) in ultrapure water adsorption of albendazole or ivermectin
obtained from Millipure purification to the sorbent, 2 mL of extract was
system (Millipore, São Paulo, SP, added to the column with vacuum
Brazil).Initially, two stock solutions application as described above. For
were prepared. First, 100 mL stock albendazole elution were used 3 ml of
solution with a concentration of 1000 acetonitrile and for ivermectin elution, 3
mg L-1 of albendazole standard, and ml of acetone were used.The obtained
another 100 mL stock solution with a sample was reconstituted with 2 mL of
concentration of 500 mg L-1 of a solution composed by acetonitrile
ivermectin standard. Then, these /water/methanol 60:10:30 (v / v / v) in
solutions were stored in decontaminated a volumetric flask of 5 mL and filtered
polypropylene flasks (Company, with a 0.22 µm syringe filter. After
Rochester, NY, USA).From the stock elution, the column was vacuum washed
solution, the working solutions were twice, using in the first wash 4 mL of
prepared in suitable concentrations to acetonitrile for three minutes and in the
the construction of the analytical second, 6 mL of hexane for two
curves.As a diluent, was used a solution minutes.
of HPLC grademethanol (Methyl The albendazole or ivermectin detection
alcohol Isocratic UV-IR-HPLC) and was performed by high-performance
chloroform (Chloroform UV/HPLC liquid chromatography with 200 series
spectroscopy, Vetec, Brazil) at ratio pump, sampling valve, 20 µL loop and
30:70 v/v, respectively, according UV / Vis detector (HPLC, Perkin
suggested by Waldia et al. (2008).The Elmer, USA).
working solutions were always prepared For chromatographic separation of
on the day of analysis and discarded at albendazole or ivermectin was used a
the end of the routine. column of 250 x 4.5 mm, 5µm particle
The mobile phase was prepared by the size (RP-C18, Thermo, USA). Each
addition of HPLC grade acetonitrile sample injected in triplicate (20 µL) was
(isocratic UV-IR-HPLC, Panreac, submitted to an isocratic elution (flow
Spain), Milli-Q water and methanol in of 1.8 mL.min-1). The albendazole or
the proportion 60:10:30 (v/v/v), ivermectin detection was performed at a
respectively (Waldia et al., 2008). temperature of 30 °C using a
After samples thawing, an aliquot of 2 wavelength of 245 nm.
mL of milk was transferred to a test The validation procedures of analysis
tube, and 2 mL of acetonitrile was method were performed based on the
added, then centrifuged at 1350 ppm for linearity parameters, accuracy
5 minutes to obtain the extract. (recovery), precision (repeatability and
The extraction procedure of albendazole partial reproducibility), detection limit
and ivermectin from the milk samples and quantification.
was performed in four steps: i)
Received on: 09/08/2018. Accepted on: 07/12/2018
4Rev. Bras. Saúde Prod. Anim., Salvador, v.20, 1 -12, e0112019, 2019 ISSN 1519 9940
http://dx.doi.org/10.1590/S1519-994020 01012019
Statistical analysis In similar studies with bovine milk
samples containing benzimidazole
The quantitative data obtained from the residues were found determination
albendazole concentration on the coefficients of 0.992 ; 0.994 and 0.999
different days of collection were using system with electrospray
submitted to analysis of variance ionization with mass detector - HPLC
(ANOVA) and the means compared by EI-MS (Xi et al., 2010);HPLC system
the Tukey test (SAS, version with mass detector–HPLC/MS (Moreno
8.0).Differences were considered et al., 2005) and HPLC coupled to a
significant at PRev. Bras. Saúde Prod. Anim., Salvador, v.20, 1 -12, e0112019, 2019 ISSN 1519 9940
http://dx.doi.org/10.1590/S1519-994020 01012019
Figure 1. Chromatograms obtained with the standard solution of albendazole (A1) or
ivermectin (B1) and with goat milk samples containing albendazole (A2) or
ivermectin (B2) residues with respective retention times (RT).
RT=2,17 RT=2,16
A1 A2
RT=4,45 RT=4,40
B2
B1
In fortified samples of bovine milk were
observed albendazole retention time of method can influence the retention time
5.86 minutes using HPLC/MS (Whelan of the evaluated residue.
et al., 2010) and ivermectin retention In all samples containing albendazole at
time of 6.9 and 11.2 minutes using different concentration levels (10, 120
HPLC-FL (Flajs et al. , 2005; Souza et or 480 µg.mL-1) the mean rate of
al., 2007). Even though these times residue recovery was 88.5% and the
were greater than those found in the mean values of repeatability and partial
present study, it is emphasized that the reproducibility were 16.9 % and 16.2%,
methodologies used were different, respectively.Similarly, in samples
including the fact that the vermifuges containing ivermectin at concentrations
were added to milk samples from of 10, 40 and 320 µg.mL-1, the mean
untreated animals. Considering the recovery residue rate was 92.5% and the
retention time as the time spent from the mean values of repeatability and partial
moment of sample injection to the reproducibility were 16.1% and 16.8%,
maximum peak observed in the in the same order (Table 1).
chromatographic system. Thus, the
internal temperature of the column, the
mobile phase used or even the injection
Received on: 09/08/2018. Accepted on: 07/12/2018
6Rev. Bras. Saúde Prod. Anim., Salvador, v.20, 1 -12, e0112019, 2019 ISSN 1519 9940
http://dx.doi.org/10.1590/S1519-994020 01012019
Table 1. Recovery rates, repeatability and partial reproducibility of analytical method
used to the analyte albendazole or ivermectin detection in goat milk1
Concentration Recovery Repeatability Partial
(µg.mL-1) (%) (%)2 reproducibility
(%)2
Albendazole
10 85,5 14,8 16,3
120 89,4 17,3 16,8
480 90,6 18,6 15,6
Ivermectin
10 95,5 16,8 14,5
40 87,8 12,6 18,7
320 94,2 18,9 17,2
1
Added standard solution of albendazole or ivermectin; 2Values expressed in relative standard
deviation.
In previous studies was observed maximum acceptable values should be
variation in the recovery residues rates defined according to the matrix,
in bovine milk, with rates ranging from methodology, analyte concentration and
68% to 85% for albendazole residues the purpose of the method (Anvisa,
(Ruyck et al., 2000), 77.0 and 97% 2003).
(Moreno et al., 2005) and 80.5% and In the present study, the detection limits
101.3% (Xi et al., 2010).For ivermectin and quantification of albendazole were
residues were obtained mean recovery 10 and 120 µg.mL-1 and ivermectin 10
rates of 78.8% (Alvinerie et al., 1994), ≥ and 280 µg.mL-1, respectively.In bovine
60.0% (Turnipseed et al., 2005) and milk, detection and quantification limits
≥84.0% (Souza et al. , 2007). of the method of 0,01- 0,5 µg.L-1 and
Analyzing these previous studies of0,1-1,0 µg.L-1, respectively (Xi et al.,
together with the present results is 2010) and 3.8 and 6.9 ng.mL-1 (Ruyck
plausible to admit that the recovery rate et al., 2000). For avermectins using
of albendazole residues and macrocyclic HPLC-FL, detection and quantification
lactones may be influenced by the limits of 5 and 10 µg.L-1 (Souza et al.,
matrix and/or the method used. 2007), respectively, were found.
According to Anvisa (2003) the The expressive values of precision
recovery rate should be close to 100%, (repeatability and partial
but if recovery is accurate and exact, reproducibility) found in the different
smaller values are allowed. concentrations of analyte, in addition to
In bovine milk matrix, partial the recovery rate and the detection and
reproducibility values ≤14% were quantification limits reinforce the
obtained for the analyte albendazole (Xi reliability of the analytical method for
et al., 2010).In ivermectin residue study, residue determination of albendazole
also in bovine milk matrix, repeatability and ivermectin in goat milk.
values ≤14.7% and partial The highest concentrations of
reproducibility ≤22% were obtained albendazole were observed in the first
(Souza et al., 2007).Although the 24 hours (101.20 + 37.4µg.mL-1), and
repeatability and partial reproducibility residue was detected in all samples
values should not exceed 15%, the evaluated up to 48 hours after drug
administration; the amount of excreted
Received on: 09/08/2018. Accepted on: 07/12/2018
7Rev. Bras. Saúde Prod. Anim., Salvador, v.20, 1 -12, e0112019, 2019 ISSN 1519 9940
http://dx.doi.org/10.1590/S1519-994020 01012019
residue 24 hours after albendazole oral route and 3.0 mg.kg-1 by
administration allowed the formation of subcutaneous route.
two groups, 50% showed a mean In a previous study, it was observed that
concentration of 68.01 ± 13.37 µg.mL-1 72 hours post drug application the
and 50% 134.36 ± 16.04 µg.mL- concentration reached an average value
1
.However, although a significant lower than 100 µg.L-1 in goat and sheep
difference between the animals about milk (Cinquina et al., 1996). In the
the amount excreted in the first 24 hours present study, the time required for
(range of 111.56 µg.mL-1), it was residual values to be 0.05), when all samples
administration, no residue was detected had values ≥51.90 µg.mL-1; the mean
in the milk. concentration in the D28 was lower than
The excretion time of albendazole in those observed in previous days
milk is variable in small and large (PRev. Bras. Saúde Prod. Anim., Salvador, v.20, 1 -12, e0112019, 2019 ISSN 1519 9940
http://dx.doi.org/10.1590/S1519-994020 01012019
The fluctuation of ivermectin µg.mL-1, respectively. This trend of
concentrations in function of time can standardization of excretion profile was
be a consequence of individual also verified in the animals that
variations in milk synthesis and remained excreting ivermectin on days
secretion processes (Cerkvenik et al., 28 and 35, whose amplitudes were 2.92
2002).These differences can be and 1.70 µg.mL-1, respectively.
attributed to differences in drug When comparing the results obtained
absorption rate, metabolic condition and with the two drenchs, it was possible to
animal body composition (Flajs et al., verify that the excretion of albendazole
2005).Considering that ivermectin and ivermectin in the milk occurred in a
fraction eliminated through milk can differentiated way. While albendazole
also be influenced by its fat content excretion occurred in high percentages
(Lanusse et al., 2009), the genetic in the first two days, ivermectin was
diversity of the Brazilian mongrerl excreted in small proportion in the first
goats can be an additional factor to be 21 days. The decrease rates of
considered in the individual differences albendazole residue at intervals of 24-
observed in the present study. 48 hours; 48-72 hours; 72-96 hours after
Although the individual metabolism drug application were 63.34%; 40.18%
caused dispersion of the excretion and 100.0%, respectively.In the
values at the initial moment, was ivermectin case, the decrease rates in
observed that the animals trended to the intervals D3-D7; D7-D14; D14-D21;
have an excretion pattern of residue in D21-D28; D28-D35; D35-D42 were 8.7%;
the period between D7 and D21.The 2.1%; 2.6%, 34.3%, 33.2% and 100%
samples amplitudes in the D3, D7, D14 respectively (Figure 2).
and D21 were 32.15; 14.8; 9.10 and 5.02
Figure 2. Concentration curves of albendazole and ivermectin residues in milk of
reated native goats.
180
160 y = 0,0049x2 - 2,0154x + 147,43 100
140 2 90 y = -0,0461x2 + 0,5902x + 57,394
R = 0,9984
80 R2 = 0,9842
Concentration (µg.mL-1)
Concentration (µg.mL )
120
-1
70
100 60
80 50
60 40
30
40
20
20
10
0 0
0 24 48 72 96 0 7 14 21 28 35 42
Time after albendazole application (hours) Time after ivermectin application (day)
Albendazole rapidly undergoes plasma half-life is 8.5 hours (Marques
extensive first-pass metabolism in the et al., 2002).The amount and excretion
liver, being transformed into time of albendazole by urine varies with
albendazole sulfoxide, the primary species; in cow, 47% of the
metabolite with antihelmintic activity; administered dose was excreted within
Albendazole sulfoxide is mainly 72 hours; in sheep, 51% of the dose was
eliminated in bile, with a small excreted in 120 hours and in pork, 75%
proportion eliminated by urine and its of the dose was excreted in 48 hours
Received on: 09/08/2018. Accepted on: 07/12/2018
9Rev. Bras. Saúde Prod. Anim., Salvador, v.20, 1 -12, e0112019, 2019 ISSN 1519 9940
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(Fao / Who, 1989). Ivermectin has low ANVISA. Agência Nacional de
metabolism, with the most dose being Vigilância Sanitária. Programa de
excreted unchanged in feces (90%), Análise de Resíduos de Medicamentos
urine (2%) and by mammary glands (5- Veterinários em Alimentos de origem
8%), with a plasma half-life of 22-28 animal - PAMVet. Relatório
hours;the ivermectin persistence by a 2004/2005: monitoramento de resíduo
long time in the organism is due to its em leite exposto ao consumo. 2006.
low plasma clearance, high affinity for 46p. Disponível em:
lipoproteins and accumulation in http://www.Anvisa.gov.br/alimentos/pa
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