Pharmacokinetics of sodium and trihydrate amoxicillin in sheep after intravenous and intramuscular administration.
- [show abstract] [hide abstract]
ABSTRACT: The pharmacokinetic behavior of sodium amoxicillin was studied after intravenous administration to six sheep and five goats to determine if there are species differences in disposition. The plasma drug concentrations vs. time following intravenous administration of 10 mg/kg were best described by the biexponential equations Cp = 42.9e-0.077.t + 3.68e-0.0134.t for goats, and Cp = 53.5e-0.06.t + 1.69e-0.015.t for sheep. The terminal disposition half-lives for sheep and goats were 46.3 and 66.9 min respectively and were not significantly different. Amoxicillin clearance for sheep and goats were 10.1 and 11.4 ml/min.kg respectively. There were no significant differences between any of the pharmacokinetic parameters measured in sheep and goats.Journal of Veterinary Pharmacology and Therapeutics 04/1992; 15(1):72-7. · 1.35 Impact Factor
- Journal of Pharmacokinetics and Biopharmaceutics 05/1978; 6(2):165-75.
- [show abstract] [hide abstract]
ABSTRACT: Statistical moments are parameters that describe the characteristics of the time courses of plasma concentration (area, mean residence time, and variance of residence time) and of the urinary excretion rate that follow administration of a single dose of a drug. The relationship between the moments of a time-course curve and pharmacokinetic profiles of drug disposition, i.e., absorption, distribution, metabolism, and excretion, is described. The moments are related to the extent and rate of bioavailability, and it is shown that they can be effectively applied to the deconvolution operation.Journal of Pharmacokinetics and Biopharmaceutics 01/1979; 6(6):547-58.
Pharmacokinetics of sodium and trihydrate amoxicillin in sheep after
intravenous and intramuscular administration
J. O. ERRECALDE?&
E. L. MARIN˜O*
*Unidad de Farmacia Clı ´nica y Farmacoterapia, Departamento de Farmacia y Tecnologı ´a Farmace ´utica, Facultad de Farmacia, Universidad de
Barcelona, Espan ˜a, Spain;?Ca ´tedra de Farmacologı ´a, Farmacote ´cnia y Terape ´utica Facultad de Ciencias Veterinarias, Universidad Nacional de La
Plata, cc 296,1900 La Plata, Argentina; INCAM, Vero ´nica-Can ˜uelas, Argentina
(Paper received 17 October 2006; accepted for publication 10 February 2007)
Prof. Eduardo L. Marin ˜o, Clinical Pharmacy and Pharmacotherapy Unit, Av. Joan XXIII s/n, 08028 Barcelona, Spain. E-mail:
Amoxicillin is a broad-spectrum penicillin with a low toxicity
widely used in many animal species for the treatment of
respiratory, digestive, skin and other infections (Palmer et al.,
1976; Keefe, 1977). It is presented as a sodium salt, that is very
soluble in water, and as a trihydrate salt that is less soluble in
water. In veterinary practice, amoxicillin trihydrate can be used
for parenteral administration. It results in a suspension, which is
more stable than sodium amoxicillin and has a slower disap-
pearance from the organism (Yeoman, 1977; Archimbault &
Pharmacokinetics studies of sodium amoxicillin have been
performed in different animals. These studies also examined
different administration routes (Carter et al., 1986; Montesissa
et al., 1988; Craigmill et al., 1992; Carceles et al., 1995;
Escudero et al., 1998; Gulland et al., 2000; Errecalde et al.,
2001). However, the literature provides little information about
the kinetic profile of amoxicillin trihydrate as a suspension drug
delivery release formulation after intramuscular (i.m.) adminis-
The objective of this study is to examine the pharmacokinetics
of amoxicillin after intravenous (i.v.) and i.m. administration of
the sodium salt and after i.m. administration of a suspension of
trihydrate salt to sheep.
The study was carried out in a total of 10 sheep weighing
between 38 and 52 kg. They were given high-quality lucerne
hay and water ad libitum during the study. Animals were
allocated to sequences of treatment according to a crossover
design: a single dose of 10 mg/kg of a dissolution of sodium
amoxicillin for i.v. and i.m. administration routes and the same
dose of a suspension of trihydrate amoxicillin for i.m. adminis-
Samples of 1 mL of blood extracted from jugular venous, were
collected in heparinized tubes, immediately centrifuged and
plasma separated was frozen at )20 ?C until analysis. Time
sampling was before 1, 5, 10, 15, 30 and 45 min and 1, 1.5, 2,
2.5 and 3 h after the i.v. administration; before 5, 10, 15, 30
and 45 min and 1, 1.5, 2, 3, 4 and 5 h after the i.m.
administration of sodium amoxicillin and before 15, 30 and
45 min and 1, 1.5, 2, 4, 6, 8, 10 and 12 h after the i.m.
administration of amoxicillin trihydrate.
Concentrations of amoxicillin in plasma were determined in
triplicate by a microbiologic plate diffusion method using
Bacillus subtilis ATCC6633 as test organism (Garrod, 1978).
Calibration curves were prepared with solutions of known
concentration of amoxicillin in sheep plasma (from 100 to
0.5 lg/mL for i.v. amoxicillin; from 25 to 0.5 lg/mL and from 5
to 0.1 lg/mL for i.m. sodium amoxicillin and trihydrate
amoxicillin respectively) and run simultaneously with test
samples. The quantification limit was 0.06 lg/mL. The corre-
lation coefficients for the regression line of the standard
solutions were 1.000, 0.998 and 0.999 respectively. The within
and between-day coefficients of variation and the accuracy of
the assay were <5% in all cases.
The kinetic analysis of amoxicillin following the i.v. and i.m.
administration of sodium amoxicillin was performed using a
compartmental approach assisted by the use of a pharmacoki-
netic data analysis computer program (MicroMath Scientific
Software, Salt Lake City, UT, USA). Polyexponential equations
were fitted to plasma concentration–time by means of nonlinear
least-squares regression analysis. The best fitting model was
chosen by minimum Akaike’s Information Criteria (AIC) (Yam-
aoka et al., 1978a). The basic pharmacokinetic parameters were
collected for both administration routes and the rapid disposition
constant (a) and the slow disposition constant (b) and the
intercompartmental micro-rate constants (K12 and K21) were
collected for i.v. administration only. It was also calculated using
standards equations the mean residence time (MRT) for both
J. vet. Pharmacol. Therap. 30, 263–266, doi: 10.1111/j.1365-2885.2007.00843.x.SHORT COMMUNICATION
? 2007 The Authors. Journal compilation ? 2007 Blackwell Publishing Ltd263
The plasma concentration of amoxicillin vs. time curves from
amoxicillin trihydrate was analyzed by noncompartmental
pharmacokinetics (Yamaoka et al., 1978b; Riegelman & Collier,
1980). Area under the concentration–time curve (AUC) from
zero to infinite time was calculated according to the trapezoidal
rule. MRT was calculated using standard equations and the peak
concentration (Cmax) and time (tmax) were obtained by visual
inspection of the experimental data. The relative bioavailability
(F) of amoxicillin was estimated by the method of corresponding
The results obtained in the study were subjected to nonpar-
ametric Wilconson test due to the fact that data did not have a
normal distribution. A probability level of P < 0.05 was
established as being statistically significant.
The mean (±SD) plasma concentration–time curves following
the i.v. administration is presented in Fig. 1. The corresponding
to the i.m. administration of sodium amoxicillin and the i.m.
administration of trihydrate amoxicillin are shown in Fig. 2. The
main pharmacokinetics parameters (mean ± SD) calculated for
each formulation and administration route are summarized in
Following i.v. administration of sodium amoxicillin, drug
concentration declined rapidly and amoxicillin disposition was
best described by a biexponential equation of the form
C(t) ¼ A0e)at+ B0e)bt, where C(t) is the plasma drug concen-
tration at time t. The plasma concentration–time curve after i.m.
administration of sodium amoxicillin was characterized by a first
order absorption and elimination processes with a biexponential
equation of the form C(t) ¼ A e)Ket)B e)Kat, where Keand Ka
were the elimination and absorption constants respectively.
The rapid disposition constant (a) was 14.36 ± 5.30 h)1, the
slow disposition constant (b) was 1.92 ± 0.48 h)1and the
elimination constant was 5.72 ± 2.26 h)1, indicating a rapid
distribution and elimination of the drug following i.v. adminis-
Peak concentration was 13.42 ± 5.36 lg/mL and reached
after 0.55 ± 0.15 h. MRT were 0.48 ± 0.15 and 1.07 ± 0.30 h
for the i.v. and i.m. administration of sodium amoxicillin
The results obtained after i.v. administration are in agreement
with the findings of other studies of amoxicillin performed in
sheep (Craigmill et al., 1992; Carceles et al., 1995). However, the
plasma levels of sodium amoxicillin vs. time after i.m. admin-
istration were best fitted to a one-compartmental model with first
order absorption and elimination rates. Drugs in which the rapid
disposition phase takes little time can produce a change in the
kinetic model according to the route of administration. When the
drug is administered outside of the vasculature, the absorption
process masks the rapid disposition phase, thus falsifying the
kinetic model. This holds true for different beta-lactam antibiot-
ics, such as cefradoxil and cefmetazole (Marin ˜o et al., 1982;
Rodriguez-Barbero et al., 1985).
Amoxicillin was more rapid absorbed after i.m. administration
of sodium salt than trihydrate. Values of mean absorption time
(MAT) (MRTi.m.–MRTi.v.) were about 0.6 and 8 h for sodium and
trihydrate amoxicillin respectively.
Regarding i.m. administration of sodium amoxicillin, Cmax
presented a mean value of 13.42 ± 5.36 lg/mL at a time of
0.36 ± 0.21 h with a rapid elimination yielding an antibiotic
plasma concentration of 0.12 ± 0.01 lg/mL 5 h after adminis-
tration. However, a greater antibiotic permanence is observed in
the plasma respecting to i.v. administration. So, the mean half-
life elimination was 0.55 ± 0.15 h after i.m. administration and
was statistically greater (P < 0.05) than the half-life obtained
after i.v. administration of sodium amoxicillin. MRT values
reaffirm this finding with 1.07 ± 0.30 h for i.m. administration
and 0.48 ± 0.15 h for i.v. administration respectively. There
were statistically significant differences between both values
(P < 0.05).
The i.m. absolute bioavailability was 69%, which was similar
to that reported in horses (67%) by Montesissa et al. (1988),
in pigeons (76%) by Escudero et al. (1998) or in chickens by
el-Sooud et al. (2004).
Following the i.m. administration of trihydrate amoxicillin,
peak concentration reached was 2.48 ± 0.54 lg/mL at 1 h after
administration. It is important to note the difference between
sodium amoxicillin and trihydrate amoxicillin administered
intramuscularly, as the later yields a significantly lower peak
concentration and at times away of the administration.
Fig. 1. Plasma concentration (mean ± SD) vs. time after intravenous
administration dose of 10 mg/kg of sodium amoxicillin to sheep.
Fig. 2. Plasma concentration (mean ± SD) vs. time after intramuscular
administration dose of 10 mg/kg of sodium and trihydrate amoxicillin to
264 C. Fernandez et al.
? 2007 The Authors. Journal compilation ? 2007 Blackwell Publishing Ltd
In comparison, i.m. administration of trihydrate amoxicillin
(Fig. 2), yielded plasma levels of 1.31 ± 0.55 lg/mL at 4 h,
0.57 ± 0.28 lg/mL at 12 h, and 0.098 ± 0.07 lg/mL at 24 h
after administration. This last value was obtained by extrapo-
lating the data from the plasma level curve.
Taking into account that MIC value for amoxicillin is about
0.25 lg/mL for most susceptible micro-organism (Brander et al.,
1991), it is possible to observe that serum levels are next to 3 h
above MIC after i.v. administration, <4 h after i.m. administra-
tion of sodium amoxicillin and more than 12 h after trihydrate
According to this, a slower disappearance process was
observed with the trihydrate amoxicillin suspension respecting
to sodium amoxicillin administered by the same route. However,
the absolute bioavailability of trihydrate amoxicillin suspension
was 73%, which was similar to that obtained with sodium
These findings and the difference obtained for MRT values can
contribute significantly in veterinary practice because sometimes
the administration of drugs cannot be made as frequently as
desirable drug. The use of suspensions, such as these of our
study, could prolong the dosage interval for 24 h, for example, as
can be seen in Fig. 3 where a multiple dose regimen is simulated.
As it can be shown kept plasma levels of amoxicillin trihydrate
let increase outstandingly administration times. Nevertheless, it
would have to confirm if an increase of the dose would be
necessary to offset values of plasma concentration at times next
Archimbault, P.H. & Boutier, C. (1981) Amoxiciline chez le veau: bio-
disponibilite ´ compare ´e de pre ´parations injectables. Revue de Medecine
Veterinaire, 132, 51–56.
Brander, G.C., Pugh, D.M., Bywater, R.J. & Jenkins, W.I. (1991) Veter-
inary Applied Pharmacology and Therapeutics, 5th edn. Baillie `re Tindall,
Carceles, C.M., Escudero, E. & Baggot, J.D. (1995) Comparative phar-
macokinetics of amoxicillin/clavulanic acid combination after in-
travenous administration to sheep and goats. Journal of Veterinary
Pharmacology and Therapeutics, 18, 132–136.
Carter, G.K., Martens, R.J., Brown, S.A. & Martin, M.T. (1986) Phar-
macokinetics of sodium amoxicillin in foals after intramuscular ad-
ministration. American Journal of Veterinary Research, 47, 2126–2129.
Craigmill, A.L., Pass, M.A. & Wetzlich, S. (1992) Comparative pharma-
cokinetics of amoxicillin administered intravenously to sheep and
goats. Journal of Veterinary Pharmacology and Therapeutics, 15, 72–77.
Errecalde, J.O., Carmely, D., Marin ˜o, E.L. & Mestorino, N. (2001) Phar-
macokinetics of amoxycillin in normal horses and horses with
experimental arthritis. Journal of Veterinary Pharmacology and Ther-
apeutics, 24, 1–6.
Escudero, E., Vicente, M.S. & Carceles, C.M. (1998) Pharmacokinetics of
amoxicillin/clavulanic acid combination after intravenous and in-
tramuscular administration to pigeons. Research in Veterinary Science,
Garrod, L.P. (1978) Foreword. In Laboratory Methods in Antimicrobial
Chemotherapy. Eds Reeves, D.S., Phillis, I., Williams, J.D. & Wise, R. pp.
iv. Churchill Livingstone, New York.
Gulland, F.M., Stoskopf, M.K., Johnson, S.P., Riviere, J. & Papich, M.G.
(2000) Amoxicillin pharmacokinetics in harbor seals (Phoca vitulina)
and northern elephant seals (Mirounga angustirostris) following single
dose intravenous administration:
dose sealing. Journal of Veterinary Pharmacology and Therapeutics, 23,
Table 1. Pharmacokinetic parameters (mean ± SD) of amoxicillin in sheep after i.v. and i.m. administration at a dose of 10 mg/kg weight
i.v. administration sodium amoxicillini.m. administration sodium amoxicillini.m. administration trihydrate amoxicillin
14.36 ± 5.30
1.92 ± 0.48
0.38 ± 0.09
5.17 ± 2.86
5.38 ± 2.98
5.75 ± 2.38
21.83 ± 8.00
0.48 ± 0.15
8.29 ± 5.93
1.37 ± 0.48
0.55 ± 0.15
13.42 ± 5.36
0.36 ± 0.21
2.48 ± 0.54
0.98 ± 0.15
1(lg/mL)h 15.05 ± 1.82
1.07 ± 0.30
1(lg/mL)h15.40 ± 1.05
8.57 ± 2.78
a and b, rapid and slow disposition rate constant after i.v. administration; t1/2b, half-life of slow disposition rate constant; K12and K21, intercom-
partmental micro-rate constants; K10, elimination constant; AUC, area under the plasma concentration–time curve from zero to infinite time; MRT,
mean residence time; Kaand Ke, absorption and elimination constant after i.m. administration; Cmax, maximal plasma concentration; tmax, time of
maximal plasma concentration; t1/2, half-life of elimination after i.m. administration.
Fig. 3. Simulation of a multiple dosage regimen following i.m. admin-
istration sodium amoxicillin every 6 h compared with trihydrate
amoxicillin every 24 h.
Pharmacokinetics of amoxicillin in sheep 265
? 2007 The Authors. Journal compilation ? 2007 Blackwell Publishing Ltd
Keefe, T.J. (1977) Toxicology studies with amoxicillin. Veterinary Medi-
cine and Small Animal Clinics, 72, 739–743.
Marin ˜o, E.L., Dominguez-Gil, A. & Muriel, C. (1982) Influence of dosage
form and administration route on the pharmacokinetic parameters of
cefradoxil. International Journal of Clinical Pharmacology, Therapy and
Toxicology, 20, 73–77.
Montesissa, C., Carli, S., Sonzogni, O. & Garlappi, R. (1988) Pharmaco-
kinetics of sodium amoxicillin in horses. Research in Veterinary Science,
Palmer, G.H., Buswell, J.F., Dowrick, J.S. & Yeoman, G.H. (1976)
Amoxycillin: a new veterinary penicillin. Veterinary Record, 99, 84–85.
Riegelman, S. & Collier, P. (1980) The application of statistical moment
theory to the evaluation of in vivo dissolution time and absorption
time. Journal of Pharmacokinetics and Biopharmaceutics, 8, 509–534.
Rodriguez-Barbero, J., Marin ˜o, E.L. & Dominguez-Gil, A. (1985) Phar-
macokinetics of cefmetazole administered intramuscularly and in-
travenously to health adults. Antimicrobial Agents and Chemotherapy,
el-Sooud, K.A., Al-Tarazi, Y.H. & Al-Batained, M.M. (2004) Comparative
pharmacokinetics and bioavailability of amoxycillin in chickens after
intravenous, intramuscular and oral administrations. Veterinary Re-
search Communications, 28, 599–607.
Yamaoka, K., Nakagawa, T. & Uno, T. (1978a) Applications of Akaike’s
information criteria (AIC) in the evaluation of linear pharmacokinetics
equations. Journal of Pharmacokinetics and Biopharmaceutics, 6, 165–
Yamaoka, K., Nakagawa, T. & Uno, T. (1978b) Statistical moment in
pharmacokinetics. Journal of Pharmacokinetics and Biopharmaceutics, 6,
Yeoman, G.H. (1977) Microbiology and bioavailability of amoxicillin.
Veterinary Medicine and Small Animal Clinics, 72, 720–738.
266 C. Fernandez et al.
? 2007 The Authors. Journal compilation ? 2007 Blackwell Publishing Ltd