The

Veterinary Journal
The Veterinary Journal 170 (2005) 339–345
www.elsevier.com/locate/tvjl

Clindamycin bioavailability and pharmacokinetics following

oral administration of clindamycin hydrochloride capsules in dogs
a,*
Georgios C. Batzias , Georgios A. Delis a, Labrina V. Athanasiou b

a
Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece
b
Veterin S.A., Aspropyrgos Attikis, Greece

Accepted 27 June 2004

Abstract

Oral bioavailability and pharmacokinetic behaviour of clindamycin in dogs was investigated following intravenous (IV) and oral
(capsules) administration of clindamycin hydrochloride, at the dose of 11 mg/kg BW. The absorption after oral administration was
fast, with a mean absorption time (MAT) of 0.87 ± 0.40 h, and bioavailability was 72.55 ± 9.86%. Total clearance (CL) of clinda-
mycin was low, after both IV and oral administration (0.503 ± 0.095 vs. 0.458 ± 0.087 L/h/kg). Volume of distribution at steady-
state (IV) was 2.48 ± 0.48 L/kg, indicating a wide distribution of clindamycin in body fluids and tissues. Elimination half-lives were
similar for both routes of administration (4.37 ± 1.20 h for IV, vs. 4.37 ± 0.73 h for oral).
Serum clindamycin concentrations following administration of capsules remained above the MICs of very susceptible microor-
ganisms (0.04–0.5 lg/mL) for 12 or 10 h, respectively. Time above the mean inhibitory concentration (MIC) is considered as the
index predicting the efficacy of clindamycin (T>MIC must be at least 40–50% of the dosing interval), so a once-daily oral adminis-
tration of 11 mg/kg BW of clindamycin can be considered therapeutically effective. For less susceptible bacteria (with MICs of 0.5–2
lg/mL) the same dose should be given but twice daily.

2004 Elsevier Ltd. All rights reserved.

Keywords: Clindamycin; Capsules; Bioavailability; Pharmacokinetics; Dogs

1. Introduction of a hydroxyl group by chlorine at the C7 position led to

Clindamycin is a semi-synthetic lincosamide that
occupies a prominent place among the antimicrobials
used against staphylococcal, anaerobic and some proto-
zoal infections in small animals (Prescott, 2000) and hu-
mans (Lewis et al., 1999; Pfefferkorn and Borotz, 1994).
Lincomycin, the parent compound, a natural fermenta-
tion product of Streptomyces spp., is a monoglycoside
with an amino-like side chain. The synthetic substitution
*
Corresponding author. Tel./fax: +30 2310999855.
E-mail address: batzias@vet.auth.gr (G.C. Batzias).
the formation of clindamycin.
The new molecule has proved to be superior in terms
of antimicrobial activity against Gram+ aerobes (cocci
and bacteria) and anaerobic bacteria with mean inhibi-
tory concentrations (MICs) ranging generally from
0.04 to 0.5 lg/mL for susceptible strains (Lamp et al.,
2002; Pankuch et al., 1993; Schaumann et al., 2000).
Some protozoa, such as Toxoplasma gondii (Pfefferkorn
and Borotz, 1994) and Neospora caninum (Lindsay et al.,
1994) are also considered susceptible.
The metabolism of clindamycin (at least in humans, as
reported by Wynalda et al., 2003) includes hepatic bio-
transformation, mediated by cytochrome P450 enzymes
(primary CYP3A) towards the bioactive metabolites
clindamycin sulphoxide and N-desmethylclindamycin.

1090-0233/$ - see front matter
2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tvjl.2004.06.007
340 G.C. Batzias et al. / The Veterinary Journal 170 (2005) 339–345
The parent compound and metabolites in humans are
mainly excreted in faeces and, to a less extent, urine.
Clindamycin has usually been regarded primarily as
a bacteriostatic agent (Dow, 1988). However, recent
studies have cast some doubt on this and reports sug-
gest that it displays concentration-independent bacteri-
cidal activity (Craig and Gudmundsson, 1996; Klepser
et al., 1997; Lewis et al., 1999) while exhibiting an in
vitro post antibiotic effect (PAE) of 0.4–3.9 h, for Sta-
phylococcus aureus (Xue et al., 1996), and 2 h for
Bacillus anthracis (Athamna et al., 2004). In vivo,
the PAE is generally longer and due to effects such
as post antibiotic leukocyte enhancement and post
antibiotic sub-MIC effect (Xue et al., 1996). Vogelman
et al. (1988) reported an in vivo PAE of clindamycin
against S. aureus, in the neutropenic mouse thigh
model, of 7.1 h.
At the molecular level, clindamycin is a classical
inhibitor of bacterial protein synthesis, by binding to
the 23S ribosomal RNA of the 50S ribosomal subunit
(Prescott, 2000). However, it seems that the target site
of clindamycin in Toxoplasma gondii is not the ribo-
somal RNA itself, but rather another rRNA molecule,
encoded by a 35-kb circular extrachromosomal genome
(Pfefferkorn and Borotz, 1994).
Clindamycin in companion animal medicine is mainly
prescribed for the treatment of superficial or deep pyo-
derma, primarily caused by Staphylococcus intermedius
(Bloom and Rosser, 2001; Harvey et al., 1993; Little-
wood et al., 1999; Scott et al., 1998), osteomyelitis (Bra-
den et al., 1987), infections of the oral cavity (Sarkiala
and Harvey, 1993) and other anaerobic infections (Berg
et al., 1984; Boothe, 1990). Clindamycin has also been
successfully used against toxoplasmosis (Prescott,
2000) and neosporosis (Ordeix et al., 2002). Clindamy-
cin hydrochloride is commercially available in formula-
tions for oral administration (capsules, tablets and oral
solution), whereas injectable formulations containing
the phosphate ester, available for human medicine, are
also used (Bishop, 2001).
The pharmacokinetics of clindamycin in the dog has
been studied (Budsberg et al., 1992; Lavy et al., 1999)
after intramuscular (IM) and subcutaneous (SC) admin-
istration (Lavy et al., 1999). Two further studies (Brown
et al., 1989, 1990) reported serum and tissue disposition
of clindamycin in cats after oral administration of an
oral solution. However, despite considerable clinical
experience, which has established clindamycin among
the most widely used antimicrobial agents, to the
authorsÕ knowledge, only scarce data exist concerning
the pharmacokinetics of clindamycin after oral adminis-
tration in the dog (Lavy et al., 2000). The objective of
the present study was to examine the pharmacokinetic
profile of clindamycin in dogs after oral administration
of clindamycin hydrochloride capsules at the dose of
11 mg/kg BW.
2. Materials and methods
2.1. Experimental animals
Six (n = 6) healthy, male, Beagle dogs weighing 12–17
kg and aged 12 months, were used in this study. All dogs
were acclimatized in the experimental facilities for a per-
iod of two months before the onset of the experiment.
They were fed on a commercial dry ration and had free
access to drinking water, although they were fasted be-
fore drug administrations. Health condition was moni-
tored continuously by clinical and laboratory
examinations. Body weight determination was con-
ducted before drug administration.
The in vivo experimental phase was carried out with
permission from the local bureau of the Hellenic Minis-
try of Agriculture (Veterinary Service) and in accord-
ance to EU directives (86/609/European Council) and
state law (1197/81 and 2015/92).
2.2. Drugs
Clindamycin hydrochloride was dissolved in phos-
phate-buffered saline (pH 7.2) to obtain a 15% (w/v)
clindamycin hydrochloride injectable solution. This
solution, sterilized through a 0.22 lm pore-size filter
(Millex-GV, Millipore S.A.), was used for the IV admin-
istration. Standard clindamycin hydrochloride CRS
(86.8% clindamycin base) was purchased from European
Pharmacopoeia. Commercially available clindamycin
hydrochloride capsules (Antirobe caps, 150 mg, Phar-
macia and Upjohn) were used for oral administration.
Eight capsules were analyzed using high performance
liquid chromatography (HPLC) to confirm clindamycin
content, which was found to be in accordance with the
value given by the manufacturer.
2.3. In vivo experimental phase
The study involved IV as well as oral administration
of clindamycin hydrochloride to all dogs, according to a
two-treatment, two-period design, using a four week
wash-out interval between the two periods. All animals
were kept fasted for 12 h before each drug
administration.
2.3.1. Period 1: intravenous administration
For the first experimental period, 11 mg/kg BW clin-
damycin hydrochloride were administered IV to all ani-
mals (Day 0), after catheterisation of the left cephalic
vein. The catheters (18 G · 51 mm Abbocath-T, Abbott)
were removed shortly after administration of the drug.
Blood samples (3 mL) were collected into plastic
tubes (S-Monovette, Sarstedt) by aspiration from the
catheterized lateral cephalic vein, prior to (t = 0 h) and
at 2, 5, 10, 15, 20, 30, 45 min, 1, 1.5, 2, 2.5, 3, 4, 5, 6,
 G.C. Batzias et al. / The Veterinary Journal 170 (2005) 339–345
8, 10, 12 and 24 h after administration. The intravenous
catheters were flushed with 2 mL 1% heparinized normal
saline after each sampling.
2.3.2. Period 2: oral administration
On Day 28, all dogs received one Antirobe capsule
(150 mg clindamycin hydrochloride). Dose normalisa-
tion from mg/animal to mg/kg BW was carried out in
each animal by dividing the total amount of clindamycin
received, by its body weight. Blood sample collection
was performed, following the technique described
above, immediately before (t = 0 h) and at 15, 30,
45 min, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 h after
drug administration.
All blood samples were allowed to stand in a dark
place for 20 min. After centrifugation at 1500g for 10
min, at 4 C, the supernatant serum was transferred into
5-mL plastic tubes and was stored at
30 C, pending
analysis.
2.4. Analytical experimental phase
Clindamycin concentrations in serum and capsules
were determined using reversed-phase HPLC with ultra
violet (UV) detection (Batzias et al., 2004). Briefly, dog
serum (0.5 mL) was deproteinized with acetonitrile (1
mL) and extracted with dichloromethane (6 mL) under
alkaline conditions. A 5-mL aliquot of the organic layer
was evaporated and the dried residue was reconstituted
in 0.5 mL of mobile phase. The injection volume was 50
lL. Separation was achieved on a MZ-Analyzentechnik
Spherisorb ODS-2 (250 · 4 mm i.d., 5 lm particle size),
C18 reversed-phase analytical column. The mobile phase
was a mixture of acetonitrile-phosphate buffer (19:81,
v/v), pH 3.5, and contained 2.5 mM tetra-n-butylammo-
nium hydrogen sulfate (TBA), as a competing base.
Phosphate salts, TBA and ortho-phosphoric acid were
all from Merck. Acetonitrile and dichloromethane were
from J.T. Baker. Analyses were carried out on a Shim-
adzu LC-10A series chromatographic system, which
operated isocratically, at a flow-rate of 1.0 mL/min.
Isocratic elution was carried out at 40 C and UV
detection was performed at 195 nm. The limit of quan-
tification (LOQ) was 80 ng/mL. Recovery ranged be-
tween 94.14% and 100.99%. Regression of accuracy
data yielded an overall mean recovery (±SEM) of
93.98 ± 0.42%, whereas precision values were better
than 4.41%.
2.5. Pharmacokinetic analysis
Non-Compartmental Analysis (NCA) based on the
Statistical Moment Theory (Gibaldi and Perrier,
1982b) was applied to determine the pharmacokinetic
parameters for each individual dog, after both IV and
341
oral administration, with the aid of WinNonlin soft-
ware, version 4.0.1 (Pharsight Corp).
The Area Under the Concentration–time curve from
time zero to the last sampling point that yielded a quan-
tifiable concentration (AUC0–last) was calculated with
the Log/Linear trapezoidal method. The last five sam-
pling points in each animal were used to determine the
first-order constant associated with the terminal portion
of the curve (kz). Terminal half life (t1/2kz) was derived as
t1/2kz = ln(2)/kz. Thus, the AUC from time zero to infin-
ity (AUC0–1) was calculated as AUC0–last + Clast/kz,
where Clast stands for the last measurable concentration.
The Area Under the first Moment Curve from time zero
to infinity ðAUMC0–1 ¼ AUMC0–last þ ðtlast  C last =kz Þ
þðC last =k2z Þ, divided by AUC0–1 provided the Mean
Residence Time (MRT). The apparent Mean Absorp-
tion Time (MAT) was the difference between the MRT
obtained after oral administration and the MRT after
IV administration.
Clindamycin oral bioavailability (F) was determined
in each animal as F = AUCoral/AUCIV · DoseIV/
Doseoral · 100%. Further pharmacokinetic parameters
determined, include total clearance (CL = Dose/
AUC0–1), volume of distribution at steady-state
(Vss = CL · MRT) and volume of distribution based
on the terminal phase (Vz = Dose/kz/AUC0–1). CL and
Vz after oral administration were initially calculated by
WinNonlin directly, as CL/F and Vz/F, respectively. To
obtain the real CL and Vz, they were corrected by F.
2.6. Statistical analysis
Descriptive statistics spreadsheet (included in Win-
Nonlin software) provided mean values (±SD) for the
pharmacokinetic parameters from all animals. Statisti-
cal evaluation of the pharmacokinetic parameters was
performed by using the SPSS software. A non-paramet-
ric Mann–Whitney test was employed to compare mean
values of parameters derived from IV and oral adminis-
tration. Means were considered significantly different at
P < 0.05.
3. Results
Mean serum concentrations (±SD) of clindamycin
after IV and oral administration are presented in detail
in Table 1. Clindamycin levels were below the LOQ of
the analytical method at 24 h, in all animals. Maximum
concentration (Cmax) after oral administration, achieved
at 1 h (0.75–1.5 h in individual dogs), was 3.25 (±0.49)
lg/mL serum.
Serum concentration–time curves of clindamycin are
shown in Fig. 1, whilst selected pharmacokinetic param-
eters (mean values ± SD), describing drug disposition
are presented in Table 2. During the terminal phase,
342 G.C. Batzias et al. / The Veterinary Journal 170 (2005) 339–345

Table 1 Table 2
Mean serum concentrations (±SD) of clindamycin in six dogs after a Selected pharmacokinetic (PK) parameters of clindamycin after a
single intravenous (IV) and oral (PO) administration of clindamycin single intravenous (IV) and oral (PO) administration of clindamycin
hydrochloride, at the dose of 11 mg/kg BW hydrochloride, at the dose of 11 mg/kg BW
Time after Mean serum PK Units IV PO
administration (h) concentrations (±SD) (lg/mL) parameter administration administration
IV administration PO administration AUC lg · h/mL 22.52 ± 4.30 16.19 ± 2.83
AUMC lg · h2/mL 119.04 ± 55.62 96.17 ± 32.01
0.033 9.40 ± 1.41 –
MRT h 5.10 ± 1.52 5.79 ± 1.05
0.083 6.64 ± 1.22 –
MATapparent h 0.64 ± 0.33
0.167 6.07 ± 1.04 –
MATtrue h 0.87 ± 0.40
0.25 5.94 ± 0.84 0.60 ± 0.56
0.333 5.66 ± 0.75 –
0.5 5.19 ± 0.50 1.89 ± 0.67 kz h
1 0.169 ± 0.045 0.163 ± 0.031
0.75 4.52 ± 0.57 2.98 ± 0.40 t1/2kz h 4.37 ± 1.20 4.37 ± 0.73
1 4.10 ± 0.68 3.25 ± 0.49 CL L/h/kg 0.503 ± 0.095 0.458 ± 0.087
1.5 3.46 ± 0.53 3.09 ± 0.41 Vss L/kg 2.48 ± 0.48
2 2.91 ± 0.50 2.59 ± 0.33 Vz L/kg 3.08 ± 0.63 2.84 ± 0.44
2.5 2.48 ± 0.41 2.14 ± 0.33
3 2.14 ± 0.34 1.93 ± 0.31 F % 72.55 ± 9.86
4 1.67 ± 0.31 1.31 ± 0.25
5 1.31 ± 0.34 1.04 ± 0.22
6 0.94 ± 0.21 0.82 ± 0.16
8 0.66 ± 0.23 0.61 ± 0.15 of the first order constant associated with drug absorp-
10 0.51 ± 0.21 0.46 ± 0.14
12 0.41 ± 0.20 0.34 ± 0.12
tion (kabs), assuming first-order absorption process (Gi-
24 <LOQ <LOQ baldi and Perrier, 1982b). However, MAT calculated as
above, does not take into account the ‘‘elimination’’
from the absorption site, mirrored in the value of F.
To obtain the true MAT (1/kabs) in each animal, the
10 iv p.o individual apparent MAT values were divided by the
individual bioavailability factors. The mean value
Clindamycin concentration (µg/mL)

(±SD) calculated was 0.87 ± 0.40 h.

4. Discussion

The wide use of clindamycin in small animal medi-

0.1
0.01
0 2 4 6
Time (h)
Fig. 1. Serum concentrations of clindamycin after intravenous and
oral administration of clindamycin hydrochloride, at the dose of 11
mg/kg BW.
the curves corresponding to the two administration
routes declined in parallel (kz(IV) = 0.169 ± 0.045 h
1,
kz(oral) = 0.163 ± 0.031 h
1), yielding similar terminal
half-lives (t1/2kz(IV) = 4.37 ± 1.20 h, t1/2kz(oral) = 4.37 ±
0.73 h). Based on the similarity of the terminal half-lives,
a correction to the value of bioavailability (72.55 ±
9.86%), was not deemed necessary (Gibaldi and Perrier,
1982a). The apparent mean absorption time (MAT) of
clindamycin (MATapparent = MRToral
MRTIV) was
0.64 ± 0.33 h. MAT can be considered as the inverse
cine, the favorable results derived from clinical studies
and the lack of pharmacokinetic data following oral
administration of clindamycin hydrochloride capsules,
provided the motivation for this study.
The rate of clindamycin absorption after oral admin-
8 10 12 14
istration of clindamycin hydrochloride capsules was
quite fast (MATtrue 0.87 ± 0.40 h). The time at which
Cmax was achieved (1 h) was comparable to values ob-
tained after SC and IM administration of a buffered
20% aqueous solution of clindamycin hydrochloride at
the dose of 10 mg/mL (Lavy et al., 1999). In the latter
study, Cmax was remarkably higher in the case of SC
administration (20.8 ± 6.2 lg/mL) than after IM injec-
tion (4.4 ± 0.5 lg/mL), the last value being closer, but
still higher than our observations (3.25 ± 0.49 lg/mL).
In another study (Budsberg et al., 1992), clindamycin
phosphate was administered IM at the dose of 11 mg/
kg BW and Cmax (5.3 ± 1.0 lg/mL) was achieved at
60.3 ± 23.9 min. Lavy et al. (2000) explored the pharma-
cokinetics of clindamycin after multiple oral dosing of
clindamycin hydrochloride gel 3% to dogs, at the dose
of 11 mg/kg BW, b.i.d. for 10 consecutive days. The
 G.C. Batzias et al. / The Veterinary Journal 170 (2005) 339–345
study displayed high between-days variability concern-
ing the values of all pharmacokinetic parameters deter-
mined. A possible drawback of all of the above studies
is that clindamycin serum concentrations were deter-
mined by use of microbiological methods which, by def-
inition, could not discriminate between the parent
compound and the bioactive metabolites (clindamycin
sulphoxide and N-desmethylclindamycin).
Drug absorption after oral administration of clinda-
mycin capsules was significantly less in extent, in respect
to bioavailability values (F = 72.55 ± 9.86%), than that
after IM (115 ± 19%) and especially after SC
(310 ± 22%) injection of clindamycin hydrochloride
(Lavy et al., 1999). The unfamiliarly high value in the
case of SC administration is somewhat hard to explain.
Even lower clindamycin bioavailability (55.07–51.48%)
has been reported in humans after oral administration
of clindamycin hydrochloride capsules (Klepser et al.,
1997).
An extensive distribution of the lipophilic clindamy-
cin has already been reported in other species, such as
man (Panzer et al., 1972) and cats (Brown et al., 1990)
by direct measurement of tissue concentrations. To de-
scribe drug disposition precisely without interference
from absorption processes, major pharmacokinetic
parameters were also obtained after IV injection. The
volume of distribution found in the present study
(Vss = 2.48 ± 0.48 L/kg) confirmed the wide distribution
of clindamycin in dogs. However, a major difference
exists between this value and the value (0.86 ± 0.35 L/
kg) provided by Lavy et al. (1999). Our findings con-
cerning CL (0.503 ± 0.095 L/h/kg) were also higher
than the value provided by Lavy et al. (1999)
(6.10 ± 1.10 mL/min/kg, corresponding to 0.366 ± 0.066
L/h/kg).
MRTIV and t1/2kz(IV) of clindamycin were 5.10 ± 1.52
and 4.37 ± 1.20 h, respectively. Lavy et al. (1999) re-
ported significantly lower respective values of
143.00 ± 34.00 min (2.38 ± 0.57 h) and 124.00 ± 57.00
min (2.07 ± 0.95 h). It is clear that the differences in
the values of Vss and CL, which govern drug elimina-
tion, had an impact on the calculation of MRTIV and
t1/2kz(IV). The similarity of terminal half lives after IV
and oral (4.37 ± 0.73 h) administration of clindamycin
hydrochloride strongly indicates the absence of a flip-
flop effect, since, during the terminal phase, elimination
exclusively limited clindamycin disposition.
The reasons for the discrepancy in the major pharma-
cokinetic parameters between the present study and the
study of Lavy et al. (1999) could include the nature of
the analytical methods employed, the different methods
used for pharmacokinetic analysis and the variation in
the body weights and the breed of the animals (12–17
kg Beagle dogs versus 4–13 kg mixed breed dogs).
The susceptibility of target microorganisms to clinda-
mycin is a key factor for the prediction of the outcome
343
of antimicrobial therapy. In general, MICs of aerobic
cocci and bacteria, with good susceptibility, range from
0.04 lg/mL, for some susceptible strains of Staphylococ-
cus aureus/intermedius to 0.5 lg/mL (Lavy et al., 1999,
Lamp et al., 2002). MIC50s for susceptible anaerobic
bacteria generally range from 0.125 to 0.5 lg/mL. Inter-
mediately susceptible microorganisms, such as isolates
of Fusobacterium spp and Clostridium perfingens, display
MIC50s as high as 4 lg/mL (Pankuch et al., 1993; Schau-
mann et al., 2000).
It has been suggested that for time-dependent antimi-
crobial agents, such as clindamycin, serum concentra-
tions should remain above the MIC of pathogen
microorganisms for at least 40–50% of the dosing inter-
val (Craig, 1998). Clindamycin serum concentrations
after IV and oral administration remain above 0.5 lg/
mL approximately for 10 h (Table 1; Fig. 1).
It would appear from our findings that for the most
susceptible microorganisms that display MIC50s <0.5
lg/mL, (especially Staphylococcus and Bacillus, against
which a prolonged PAE has been demonstrated), a dos-
age of 11 mg/kg BW PO s.i.d., using clindamycin hydro-
chloride capsules is likely to be therapeutically effective.
This dosage has been used empirically in clinical trials
with dogs suffering from superficial and deep pyoderma
(Bloom and Rosser, 2001; Littlewood et al., 1999; Scott
et al., 1998). To confirm our estimation, efficacy scores
from these studies were satisfactory (58.6–100%). On
the other hand, for less susceptible bacteria (MIC50
0.5–2 lg/mL) we recommend the same dose but to be gi-
ven b.i.d.
Whether the antimicrobial activity of clindamycin
bioactive metabolites should be considered when
performing a PK/PD evaluation has not yet been eluci-
dated. In humans, the formation of N-desmethylclinda-
mycin and its excretion in urine and faeces have been
confirmed (Wynalda et al., 2003), but the metabolite
could not be detected in the plasma of patients treated
with clindamycin (Gatti et al., 1998). In dogs, no data
exist on metabolite formation and kinetics, and any con-
tribution to clindamycin efficacy is totally unknown.
The currently suggested dosage regimens are based on
parent compound concentrations only, and the presence
of metabolite activity (if any) would only amplify the
positive therapeutic outcome. More clinical and phar-
macokinetic/pharmacodynamic (PK/PD) trials (includ-
ing data on metabolite activity) are required to
confirm the optimum clindamycin dose determination
in dogs.
Acknowledgement
The authors express their gratitude to Veterin S.A.
for kindly donating the experimental animals used in
this study.
344 G.C. Batzias et al. / The Veterinary Journal 170 (2005) 339–345
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