Ivermectin in goat plasma and milk after subcutaneous injection

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Ivermectin in goat plasma and milk after subcutaneous

injection

M. Alvinerie, Jean-Francois Sutra, Pierre Galtier

To cite this version:

Original

article

Ivermectin in

_goat

_plasma

and milk

after

subcutaneous

_injection

M

Alvinerie JF

Sutra

P

Galtier

Station de

_{pharmacologie-toxicologie,}

180,

chemin de

_{Tournefeuille, BP3,}

31931 Toulouse

Cedex,

France

(Received

18

_February

1993 ;

accepted

17 June

₁₉₉₃₎

Summary ―

The

_{pharmacokinetics}

_{and mammary excretion of ivermectin} were determined in

_goats

following

a

_single

sc administration

_{(0.2 mg/kg).}

Kinetic

_analysis

of

plasma

and milk levels was per-formed

_using

a

_{1-compartment}

model. The maximum

_plasma

concentration of 6.12

_ng/ml

occurred at 2.85 d ; the half-life of 4.03 d was similar to the value in

_{sheep (3.68 d).}

Ivermectin was detected in the milk at the first

_sampling

time and thereafter for at least 25 d.

_Comparison

of the milk and

plas-ma data shows the

_{parallel disposition}

of the

_drug

in milk and

plasma

with a

_milk-plasma

concentra-tion ratio of 1.08 ± 0.23. In

conclusion,

the

_persistence

of the

_drug

in

_plasma

is reflected in the dura-tion of the presence of ivermectin in milk.

ivermectin /

plasma

I milk /

goat

Résumé ― Ivermectine dans le

_plasma

et le lait de chèvre

après

une

_injection

sous-cutanée. La

_{pharmacocinétique}

et l’excrétion mammaire de l’ivermectine ont été déterminées chez la chèvre

après

une

_injection

sous-cutanée du médicament

_{(0,2 mglkg). L’analyse}

de l’évolution des concen-trations dans le

_plasma

et le lait a été réalisée selon un modèle

_{monocompartimentaL}

La concentra-tion maximale

_plasmatique

était de 6,12

nglml

obtenue

2,85 j après l’injection,

la demi-vie était de 4,03

j,

ie une valeur

_comparable

à celle obtenue chez le mouton

_{(3,68 j).}

L’ivermectine a été détec-tée dans le lait

_depuis

le

premier prélèvement

et

_pendant

au moins 25

_j.

La

_comparaison

_des para-mètres

_{pharmacocinétiques}

démontre l’évolution

_parallèle

des concentrations dans le lait et le

plas-ma, avec un

rapport

de 1,08 ±

0,23.

En

conclusion,

la lente élimination

_plasmatique

de l’ivermectine est

_largement

reflétée dans la durée de sa

_présence

dans le lait.

INTRODUCTION

Ivermectin

_{(22, 23-dihydroavermectin B1a)}

is a

_{semi-synthetic}

derivative of a

macrocy-clic lactone

_{produced by Streptomyces}

avermitilis. Ivermectin is an

_{exceptionally}

potent drug

with a broad

_spectrum

of

activ-ity against gastrointestinal

nematodes and

lungworms

in

cattle, horses,

goats,

dogs

and swine

_(Campbell

and

_Benz,

_1984).

The

_{pharmacokinetics}

of the

_drug

differ

ac-cording

to the animal

_species,

formulation

and route

of administration

_(Lo

et al, 1985 ;

Wilkinson et

_al,

_1985).

It

is

_essential,

for a

drug

that is used so

_extensively,

to assess

possible

health hazards

due to residues.

Although

ivermectin is not recommended for administration to

_lactating

_goats,

uncon-ventional use is

_possible.

The

_present

study

was

_designed

to

_compare

the

phar-macokinetics

of ivermectin in

_plasma

and milk

of

_goats

_receiving

a subcutaneous

ad-ministration.

The

_findings

are

_compared

with results

obtained

_by

_using

other routes

of administration

_(Scott

et

_al,

_1990).

In

addi-tion,

the consequences of the mammary

ex-cretion of ivermectin are discussed.

MATERIALS AND METHODS

Animals

Five cross-bred

lactating

goats

(40-59 kg)

con-sidered at the end of the

_{lactating period}

(344-696 ml milk per

day)

were maintained

indoors,

and administered ivermectin

_according

to the manufacturer’s recommendations

(IVOMEC,

ovins, MSD, Paris,

France)

ie 0.2

_{mg/kg injected}

sc.

_Samples

of blood and milk were collected from each animal at 0.3 ; 1-7; 9; 11; 13; 15; 17; 19; 21; 23 and 25 d after

_drug

administration.

Following

centrifugation

of blood

_samples,

the

plasma

was removed and stored at -20°C until

analysis.

Milk

_aliquots

were collected each

morning

in

_glass

bottles and transferred to 5-ml tubes stored at-20°C before

_analysis.

Analysis

Both the

plasma

and milk

samples

were

anal-yzed

for ivermectin concentration

using

a

previ-ously

described method

(De Montigny

et

al,

1990).

One ml acetonitrile was added to 1 ml

plasma

or milk. After

mixing

for 20

min,

the solu-tions were

_centrifuged

at 2 000 g for 2 min and the

_supernatants

_applied

to an Absorbex C18 8

cartridge pretreated

with methanol

_{(2 ml)}

and water

_{(2 ml).}

The column was washed with 2 mi

H

2

0/Me

OH

_(75:25)

and ivermectin eluted with 1 ml MeOH. This eluate was

_evaporated

to

dry-ness under a

_gentle

stream of

nitrogen,

and the

dry

residue was dissolved in 100

_pl

N-methylimidazole

solution in acetonitrile

(1:1,

v/

v).

To initiate the derivatization, 150

_pl

trifluoroa-cetic

anhydride

solution in acetronitrile

_{(1:2, v/v)}

was added. After

_completion

of the reaction

(<

30

s),

an

_{aliquot (100 pl)}

of this solution was

injected directly

into the

chromatograph.

The mobile

_phase

consisted of acetic acid

_(0.2%

in

water)

methanol acetonitrile

_{(4:32:64 ;}

_v/v/v)

pumped

at a flow rate of 1.5 ml/min

through

a

supelcosil

C18 column

₍₃

_pm, 4.6 mm id x 150

mm)

with fluorescence detection at an excitation

wavelength

of 365 nm and an emission

wave-length

of 475 nm

_(RF

551 fluorescence detector,

Shimadzu, Kyoto,

Japan).

The limit of

_{quantification}

of the method was 0.05

_ng/ml

in

plasma

and milk, with a coefficient of variation of 4.0%

(inter-day variability).

Data

_analysis

Equation [i] corresponding

to a

_{1-compartment}

model with an

_{absorption phase}

was

_separately

fitted to the

plasma

and milk data.

In this

equation,

A

1

and A

2

are the

intercepts,

C is the

plasma

or milk concentration at time t, ka

(per min)

is the first order rate constant of iver-mectin

absorption and

(per min)

is the first or-der rate constant for ivermectin elimination.

Pharmacokinetic

_analysis

of the individual animal data were carried out

using

a _program

by

Wilcoxon’s test for

paired

data. P values

< 0.05 were considered to be

significant.

RESULTS

The mean concentrations of ivermectin in

plasma

and milk of the 5

_goats

adminis-tered the

_drug

sc are shown in

_figure

1. Ivermectin increased

_slowly

to

reach,

after 2.8

d,

maximal concentrations of 6.12 and 7.26

_ng/ml

in

_plasma

and

milk,

respectively

(table I).

All concentrations decreased

progressively

thereafter. The

_milk/plasma

ivermectin ratio determined

_by

_using

area under the curve

_(AUC)

values was 1.08 ± 0.23.

Calculated

_{pharmacokinetic parameters}

are shown in table I. There were no

signifi-cant differences between

_plasma

and milk

parameters.

The

_absorption

half-life was

1.2

d,

whereas the elimination

half-life

was

= 4 d. Similar values for mean residence

time were obtained in the 2 fluids

₍₇

-7.8

d),

and the AUC values were similar as

well

₍₆₀

_nge

_d

_em

_l

_-1).

_).

DISCUSSION

The results confirm the

_prolonged

persis-tence of the

_drug

in the

_plasma.

The value of the

half-life

_{(4.03 d)}

is similar to those

previously

reported

(Prichard

et

al,

1986)

in

_{sheep (3.68 d)}

and

horses

_{(3.66 d)}

fol-lowing

a

similar

sc

dose.

_Concerning

the

AUC

calculation,

our value

₍₅₇

_nged-mi-

₁

or

1368

_ngeh-ml-

₁

₎

_{appears 2.8-fold}

_higher

than that

_previously

determined in

goats

following

po administration of the same

dose

_(Scott

et al,

1990).

Such a difference in the

_{systemic availability}

of the

_drug

be-tween sc and oral administration has

al-ready

been described in

_sheep

with a ratio of 2.64

_(Marriner

et

_al,

_1987).

This

attrib-uted to

_degradation

of the

_drug

in the ru-men

_according

to Prichard et al

_(1986),

who demonstrated that intraabomasal ad-ministration

of

ivermectin to

_sheep

result-ed in 100%

_{systemic availability,}

whereas

intraruminal administration resulted

in

_only

25%

_{plasma availability.}

Ivermectin is a

_{highly lipid-soluble}

chemical

_(Lo

et al,

1985). Consequently,

it is not

_surprising

that it is excreted in milk. In

studies

_using

ewes

_(Marriner

et

al,

1987)

or cows

_(Alvinerie

et

_al,

1987;

Bo-gan and Me

Kellar,

1988),

the concentra-tion of ivermectin in milk was found to be similar to the

_plasma

concentration,

which is in

_good

accordance with our results.

Fol-lowing

oral or pour-on administration

(Scott

et al,

_1990),

the excretion

_pattern

of

ivermectin

is

similar.

lvermectin could be detected in the milk for 25 d after treatment. The

_product

of

ivermectin concentration and individual milk

_{yield during}

the

_experiment

amounted to an

_average

_drug

_recovery

in milk of 0.31 ± 0.21 % of the administered dose. This

re-sult

can

be

_compared

to 4% of the

dose

in

sheep (Marriner

et

al,

1987)

and

5.46%

in

cows

_(Toutain

et

al,

1988).

This

_large

dif-ference appears to be related to

differenc-es in the volume of milk

_produced

in the various

_species,

or to fat content of the milk.

In

conclusion,

the _{presence and}

persis-tence of ivermectin residues in milk

de-serve attention. Ivermectin acts

_mainly

on

y-amino-butyric

acid

_{(GABA)-mediated}

nerves which are

_mainly

_present

in the central nervous

_system

of mammals

(Campbell

et

_al,

_1983).

This

_drug

_appears

to be

_{generally safe,}

however,

since it does not

_readily

cross the adult blood-brain barrier. The

_safety

_margin

in

_target

species

is, therefore,

=

10-fold

_greater

than

the recommended

_therapeutic

dose

(Ben-net,

1986).

Nevertheless,

attention must be

_paid

to factors

_affecting

the blood-brain barrier

_{permeability,}

in terms of

_species

(Hoy

et al,

1990)

or

_age

_differences,

partic-ularly

in the newborn in which this

physio-logical

barrier is known to be

_poorly

devel-oped.

Consequently,

the

_potential

use

of

ivermectin

in

_developing

countries in which

prolonged

breast

_feeding

is

_frequent

should encourage

a

_{thorough analysis}

of

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JF,

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P,

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JA,

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(1988)

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