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Comparative biliary and serum kinetics of doxycycline after oral and intramuscular routes with special reference to its unique entero-hepatic circulation in turkeys

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Comparative biliary and serum kinetics of doxycycline
after oral and intramuscular routes with special reference
to its unique entero-hepatic circulation in turkeys
K. Abo-EL-Sooud1*; G.A. Swielim2; Y.R. Wally2 and Samar M. EL-Gammal2
1Pharmacology department, 2Anatomy and Embryology department, Faculty of Veterinary Medicine,
Cairo University, Giza /Egypt. P.O. Box 12211, Giza, Egypt. Fax: 0020235725240 002035710305.
.
K. Abo-EL-Sooud* (Corresponding author)
1Pharmacology Department, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
Tel: +201066756870 E-mail: kasooud@cu.edu.eg
Abstract
The present investigation was conducted to compare bile and serum concentrations of doxycycline
(DOX) in turkeys after single intramuscular (IM) and oral administrations of 20 mg/kg body weight (b.w.).
Furthermore, the entero-hepatic circulation and absolute bioavailability from gastrointestinal tract of DOX
after oral dose were accessed. Three groups of male turkeys of five each received DOX at a dose rate of 20
mg/kg b.w. intravenously, intramuscularly and orally. Samples of serum and bile excreted were taken at
predetermined intervals during 6 h. DOX concentrations of were determined by a reverse phase high-
performance liquid chromatography (HPLC) with UV detection at 347 nm. After intravenous (IV) injection
the elimination half-life (T1/2), the total body clearance (Cltot) and the volume of distribution (Vss) were
3.90 h, 0.55 L/h/kg and 2.39 L/kg, respectively. The maximal serum concentrations (Cmax) of DOX in
turkeys were 4.38 and 3.17 µg/ml, with time to peak concentration (Tmax) values of 0.74 and 1.00 h and
absolute bioavailability were 71.83 % and 48.81 %, after IM and oral administrations respectively. The bile
concentrations were up to 100 times higher than those in serum. The cumulative biliary excretion of the
administered dose DOX was about 7% and 3% recovered from the bile within the first 6 hr after IM and
oral dosing, respectively. After oral dose the entero-hepatic circulation model is based on the classical one
compartment model with bile elimination half-life (T1/2k1g) of 5.36 h and the maximal bile concentrations
(Cmax) was 222.39 µg/ml. Therefore DOX could be relevant for treatment of cholecyctitis and enteric
infectious diseases.
Keywords: Doxycycline, Bile, Pharmacokinetics, Entero-hepatic, Turkeys.
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1. Introduction
Although the pattern of infection in biliary disease, the microorganisms involved, and the spectrum;
pharmacokinetics of potentially effective antibiotics, bacteria are often difficult to eradicate from the bile.
The secretion of antibiotics into bile and of their efficacy once there should be helpful in choosing the best
therapeutic regime (Dooley et al., 2011). A complete profile of biliary and serum concentrations can only
be made in animals with biliary drainage. The broad use and complete acceptance of DOX is due to its
advantageous pharmacokinetic properties compared because of higher lipid solubility in comparison to
other tetracyclines and better bioavailability from the gastrointestinal tract. DOX is relatively stable in
aqueous solutions and has a broad spectrum of activity against gram-positive and gram-negative aerobic
bacteria (Shaw & Rubin.. 1986: Goren et al., 1988). Tetracyclines are bacteriostatic chemotherapeutic
agents which bind primarily to the 30S ribosomal subunit, where they inhibit protein synthesis by blocking
the binding of aminoacylated tRNA to the ribosomal acceptor (A) site (Chopra & Roberts, 2001). DOX is
also active against Chlamydia spp., Rickettsia spp., Mycoplasma spp., Pasteurella multocida, E coli, and
protozoa (Pijpers et al., 1989). It is preferred to other tetracyclines because of its higher oral absorption,
high tissue concentrations and long persistence in orally treated animals (Anadón et al., 1994). The
pharmacokinetics of DOX is described in different bird species such as chickens (Poapolathep et al., 2005
& Yang et al., 2012), turkeys (Santos et al., 1996), ducks (Bratoev et al., 2016), pigeons (Dorrestein et
al., 1991) and ostriches (Abu-Basha et al., 2006). No references have been found concerning bile excretion
of DOX in turkeys after IM and oral routes, With this background, the aim of the present study was to
compare bile and serum concentrations of DOX in turkeys after single IM and oral administrations of 20
mg/kg b.w. Additionally, to evaluate the pharmacokinetics, entero-hepatic circulation and bioavailability of
DOX after both routes of administration.
2. Materials and methods
2.1 Drug
The working standard powder of doxycycline hydrochloride (99.8%) was kindly provided by Pharma
Sewed (Jordan). The drug was dissolved in dissolved in water to a final concentration of 50 mg/ml prior to
administration.
3
2.2 Turkeys:
Seventeen male native Black Baladi breed turkeys weighing between 3.5 and 4 kg, were obtained 2 weeks
before the start of the study. During acclimatization (at least 2 weeks before starting the experiment to
ensure the complete withdrawal of any residual drugs) and subsequent treatment periods, all turkeys had
free access to water and antibacterial-free food. The animal house temperature was maintained at 22±2 0C
and humidity at 4055%. The study was approved by the Animal Care and Use Committee at the Faculty of
Veterinary Medicine, Cairo University.
2.3 Experimental design
Fifteen turkeys were divided into three groups of five birds each. DOX were administered at a dose level of
20 mg/kg in all groups. Group 1 turkeys were given a single IV injection through the right wing vein.
Group 2 turkeys were given a single IM injection in the pectoral muscles. Group 3 turkeys received a single
oral dose into the crop using thin plastic tube attached to a syringe.
2.4 Sampling
Blood samples (0.5 mL each) were taken via indwelling catheter into Vacutainers (Becton Dickinson
vacutainer Systems, Rutherford, NJ, USA), from the right wing vein at 0 (blank sample), 0.16, 0.25, 0.5,
1, 2, 4, 6, and 6 h in all groups. Serum was separated by centrifugation at 2000g for 10 min and stored at -
20 0C until assayed. Both bile ducts were cannulated and the bile volume excreted was collected at the
same intervals. The volume of bile samples was measured and an aliquot was immediately frozen until the
time of assay. The remaining two birds were used for obtaining antibacterial free serum and bile that are
necessary for standard curve.
2.5 Drug analysis
The serum and bile concentrations of DOX were determined by a reverse phase high-performance liquid
chromatography (HPLC) using the method described by Ruz et al. (2004), briefly. The samples were
chromatographed on a narrow-bore C18 column (Phoenix 150 mm × 2.1 mm) using a mobile phase with
55% acetic acid (5%), 25% acetonitrile and 20% methanol. The drug was detected 347 nm and the run time
was 4.10 min. Linearity was confirmed in the concentration range 0.480 µg/ml for DOX quantification in
serum and from 1 to 800 µg/ml.
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2.6 Calibration curve
The calibration curve of serum was prepared with seven different concentrations between 0.001 and 100
µg/ml using blank turkey serum and bile. A calibration curves were obtained by plotting the peak area
versus the nominal concentrations. The standard curves of DOX in turkey serum and bile were linear, lying
between 0.001 and 20 µg/ml. The peak area of unknown specimen (peak area of DOX) was compared with
that of the standard.
2.7 Sample preparation procedure
A 20 µL aliquot serum samples were transferred to 13 mm × 100 mm conic tubes and spiked with the
external standard DOX. Then, 20 µl acetonitrile was added to the tubes. The tubes were capped, vortex-
mixed for 1 min., and centrifuged at 3000 rpm and 4 0C for 10 min. The supernatants were transferred to
limited volume autosampler vials, diluted with a mixture of methanolacetic acid (1:1), capped and placed
on the HPLC autosampler. A 50 µl aliquot of the supernatant was injected onto HPLC column.
2.8 Pharmacokinetic analysis
Serum concentrations of DOX after IV, IM and oral administrations were subjected to a compartmental
analysis using a nonlinear least-squares regression analysis with the help of a PKSolver, China
Pharmaceutical University, Nanjing, Jiangsu, China (Zhang et al., 2010) a freely available menu-driven
add-in program for Microsoft Excel written in Visual Basic for Applications (VBA), for solving basic
problems in pharmacokinetic (PK) and pharmacodynamic (PD) data analysis. The area under the
concentration vs. time curve (AUC0–∞) was calculated using the linear trapezoidal rule and systemic and
relative bioavailabilities (F) were calculated according to the following equations: F = [mean AUCoral or IM /
mean AUCIV] X 100.
After oral dose the enterohepatic circulation model is based on the classical one compartment model. As
shown in Figure 1, according to Funaki, (1999) as ka is the first-order rate constant for drug absorption
from the gastrointestinal (GI) tract, k1g is the first-order rate constant for drug excreted into the bile, and k10
is the elimination rate constant of drug from systemic circulation. In contrast to the common
pharmacokinetic model, release of bile is assumed to occur as a bolus at the time of expulsion from the gall
bladder (Ttom) into the GI tract.
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2.9 Statistical analysis
The statistical analysis was performed using the SPSS® 10.0 software package (SAS, Cary, NC, USA).
Results are presented as arithmetic mean ± standard deviation (SD). The nonparametric Wilcoxon test was
used to compare the parameters obtained after oral and IM administration. Means were considered
significantly different at p< 0.05 and P<0.01.
3. Results
The serum concentration-time profile of DOX after IV injection is fitted to an open two-compartment
model (Figure 2). The pharmacokinetic parameters following IV administration were calculated from the
individual serum concentration-time profiles (Table 1). After intravenous (IV) injection the elimination
half-life (T1/2), the total body clearance (Cltot) and the volume of distribution (Vss) were 3.90 h, 0.55
L/h/kg and 2.39 L/kg, respectively. The ratios of k12 and k21 represented the micro-rate constants of DOX
transfer between the central and peripheral compartments were 3.91 and 0.71 h-1 in turkeys, respectively.
This indicated very good drug distribution to the different tissues.
Mean serum concentrationtime curves of DOX in turkeys following IM and oral routes are illustrated in
Figure 3 and their corresponding pharmacokinetic parameters are presented in Table 1. The bile
concentrations were up to 100 times higher than those in serum. The cumulative biliary excretion of the
administered dose DOX was about 7% and 3% recovered from the bile within the first 6 hr after IM and
oral dosing, respectively. The maximal serum concentrations (Cmax) of DOX in turkeys were 4.38 and 3.17
µg/ml, with time to peak concentration (Tmax) values of 0.74 and 1.00 h and absolute bioavailability were
71.83 % and 48.81 %, after IM and oral administrations respectively.
Figure 1: Enterohepatic circulation model according to Funaki, (1999)
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After oral dose the enterohepatic circulation model is based on the classical one compartment model. All
the calculated parameters of bile excretion are shown in Table 2. The bile elimination half-life (T1/2k1g) was
5.36 h and the maximal bile concentrations (Cmax) of DOX in turkeys was 222.39 µg/ml was attained at
time to peak concentration (Tmax) values of 1.42 h.
4. Discussion
After IV injection the serum concentration-time profile was best described by an open two-compartment
model. The volume of the central compartment and the apparent distribution volume were similar to those
reported in younger turkeys (Santos et al., 1996) and ducks (Bratoev et al., 2016) but were much lower
than that reported for chickens (Anadón et al., 1994) and for ostriches (Abu-Basha et al., 2006). This
could be attributed to different patterns of serum protein-binding and method of DOX estimation. The
values of volume of distribution and the micro-rate constants of drug transfer between the central and
peripheral compartments (k12) suggested very good drug distribution in different tissues and body fluids.
With the high lipophilic character of DOX, it would be expected to be distributed widely fat containing
tissues. The total body clearance was (0.55 L/h.kg) slower than reported in ostriches (0.15 L/h.kg; Abu-
Basha et al., 2006), laying hens (0.10 L/h.kg; Yang et al., 2016) and younger turkeys (0.09 L/h.kg; Santos
et al., 1996) but was quite similar to that reported in ducks (0.48 L/h.kg Bratoev et al., 2016). The
difference of the pharmacokinetics parameters among poultry is somewhat common and may attributed to
the inter-species variation, assay methods used, time intervals of blood samplings, health status and age of
the birds.
The maximal serum concentrations (Cmax) of DOX in turkeys after oral dosing was 3.17 µg/ml with time to
peak concentration (Tmax) values of 1.00 h. This value was statistically significant greater than reported in
ducks (Bratoev et al., 2016) after the single dose of 15 mg/kg and lower than the value reported in younger
turkeys (Santos et al., 1996) after dose of 25 mg/kg. This may be due to dose difference and adsorption of
DOX in the gastrointestinal tract epithelium.
In this respect, Abu-Basha et al., 2006 found that after the single IM and oral administration of DOX (15
mg/kg b.w.) in ostrich, the Cmax of 1.35 and 0.30 μg/ml at 0.75 and 3.03 h, respectively. The absolute
bioavailability was 48.81 %, after oral administrations. The value was similar to those reported by Anadón
et al. (1994) in 6-week-old chickens (42.8%) while are greater to those reported by Abu-Basha et al., 2006
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in ostriches (17.52%) and by Bratoev et al., 2016 in ducks (18.8%). DOXmetal ion complexes are
unstable at acid pH, therefore more DOX enters the duodenum for absorption interferes with mainly iron,
calcium and magnesium present in the food may be responsible for a reduced bioavailability from
gastrointestinal tract (Kucers et al., 1997). In addition, food has less effect on absorption than on
absorption of earlier drug
This study also clearly shows that DOX is excreted into the bile even after IM and oral administration. In
general the mean value of the biliary elimination ratios for numerous drugs has been established to be near
5% of the dose administered (Baggot, 2007). In the present study, biliary elimination within 6 hr reached
7% and 3 % of both doses given (20 mg/kg), respectively. Similar observations have been described for
tetracycline in chickens (Serrano, et al., 1999) where after oxytetracycline administration, 3.28% of the
dose had been eliminated by the biliary route in hens. This fact can be attributed to the transfer process
associated with passive diffusion. A higher value than this ratio has been found for chlortetracycline in
turkeys with 8.5% of the dose eliminated by the biliary route at 4 h after administration (Dyer, 1989);
however after oxytetracycline administration only 2.15% of the dose was eliminated via the bile by 6 h in
turkeys. Escudero et al. (1994) determined 0.5 mg/mL to be the oxytetracycline minimum inhibitory
concentration (MIC) for most susceptible pathogens.
DOX is not metabolized and it is excreted mainly via the bile (Agwuh & MacGowan, 2006), in divergent
to other antibacterials like fluoroquinolones that are metabolized and excreted via urine and bile (Buechler
& Weiss, 2011).
The mean half-life of DOX biliary elimination (5.36 h) in the present study was longer than those reported
for oxytetracycline in chickens (1.84 h) by Serrano et al., 1999. The maximal bile concentrations (Cmax) of
DOX in turkeys was 222.39 µg/ml was attained at time to peak concentration (Tmax) values of 1.42 h. The
higher values observed in bile suggest that biliary elimination is a significant route of elimination for DOX
in turkeys. In addition to this, numerous studies have shown species differences in elimination processes
owing to several factors: body size, temperature and age (Lashev et al., 1995).
The molecular weight (MW) of a compound is a key factor determining the extent of biliary vs. non-biliary
excretion. Compounds covering a wide range of MW (150 to > 700) demonstrated an increase in the
proportion of compounds excreted in the bile vs. urine as the MW increased (Toutain et al., 2010). In
8
general, MW that is close or >500 Dalton, is considered a cholephilic compound and well secreted in bile
(Dooley et al., 2011). Furthermore, Baggot, (2007) stated that compounds excreted in bile have a degree of
polarity that enables them to be transported by a carrier-mediated process from hepatic parenchymal cells
into bile. Drugs and drug metabolites excreted in bile enter the duodenum, from which some (depending on
their lipid solubility) may be reabsorbed by passive diffusion.
As the MW of DOX hydrochloride is about 480 is very close to 500 Da it was expected to excrete in the
bile fairly. After oral dose the enterohepatic circulation model is based on the classical one compartment
model with bile elimination was evident. Few studies have questioned the existence of an enterohepatic
circulation for DOX in poultry. Nevertheless, enterohepatic circulation, which leads to a longer persistence
of DOX in the body, would increase the availability of the compound. This has to be taken into
consideration when estimating the magnitude of the first-pass elimination, which otherwise tends to be
underestimated.
In conclusion, the difference found between pharmacokinetic properties of DOX in turkeys and in other
avian species illustrates the importance of the pharmacokinetic studies for establishing a proper dosage
regimen. Concentrations of DOX in bile were much higher than the MIC of most susceptible organisms; in
addition to this an enterohepatic cycle may also be established. Therefore this route could be relevant for
treatment of cholecyctitis and enteric infectious diseases. Although the IM route is not usual in clinical
practice in poultry, these results can be used as a reference of DOX biliary excretion after extravascular
administration rather than oral route to turkeys.
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Table 1: Mean ± SD serum pharmacokinetic parameters of DOX in turkeys (n=5) following IV, IM and
oral administrations at a dose rate of 20 mg/kg b.w.
NA : Not applicable; A: Intercept of the distribution line with the concentration axis; B: Intercept of the
straight line of elimination phase with the concentration; : distribution rate constant; T1/2: distribution
half-life; T½ab: absorption half-life; : Elimination rate constant; T1/2 (T½el): elimination half-life; kel:
Elimination rate constant; C0 = The concentration of drug in serum at time zero time; K12: First order
transfer rate constant for drug distribution from central to peripheral compartment; K21: First order transfer
rate constant for drug distribution from peripheral to central compartment; Vc : Volume of distribution of
central compartment; Vdss: volume of distribution; Cltot: total body clearance; AUC: area under the curve by
the trapezoidal integral; AUMC: area under moment curve by the trapezoidal integral; MRT: mean
residence time; Vdss volume of distribution at steady state: Cmax: maximum serum concentration; Tmax: time
to peak concentration; F%: bioavailability Values of oral significantly different form IM at * P<0.05,
**P<0.01.
Parameter
Unit
I/V
I/M
Oral
A
μg/ml
49.11 ± 2.58
147.70 ± 13.14
89.97 ± 4.56*
( kab)
h-1
5.92 ± 0.88
1.52 ± 0.31
0.79 ± 0.04*
B
μg/ml
5.05 ± 1.10
1.49 ± 0.82
0.82 ± 0.66
h-1
0.178 ± 0.09
NA
NA
kel
h-1
1.48 ± 0.34
0.121 ± 0.09
0.155 ± 0.07
k12
h-1
3.91 ± 0.84
NA
NA
k21
h-1
0.71 ± 0.11
NA
NA
T1/2 T1/2ab
h
0.12 ± 0.05
0.45 ± 0.12
0.88 ± 0.15
T1/2 T1/2el
h
3.90 ± 0.89
5.7 ± 0.95
4.45 ± 0.65
C0
μg/ml
54.15 ± 2.11
NA
NA
Vc
L/kg
0.37 ± 0.10
NA
NA
Cltot
L/h/kg
0.55 ± 0.08
NA
NA
Tmax
h
NA
0.74 ± 0.11
1.00 ± 0.13
Cmax
μg/ml
NA
4.38 ± 1.10
3.14 ± 0.88
AUC0-
g•h/ml
36.63 ± 3.10
26.31 ± 2.33
17.88 ± 1.21*
AUMC
g•h2/ml
160.65 ± 14.12
129.86 ± 10.44
114.42 ± 8.77
MRT
h
4.39 ± 0.79
7.90 ± 0.55
6.71 ± 0.71
Vdss
L/kg
2.39 ± 0.52
NA
NA
F
%
NA
71.83 ± 4.55
48.81 ± 3.81**
12
Table 2: Mean ± SD of Pharmacokinetic parameters of the enterohepatic circulation model of DOX bile
excretion in turkeys (n=5) following oral dose rate of 20 mg/kg b.w.
ka is the first-order rate constant for drug absorption from the gastrointestinal (GI) tract, k1g is the first-order
rate constant for drug excreted into the bile, and k10 is the elimination rate constant of drug from systemic
circulation T1/2ka: absorption half-life;; T1/2k1g : bile elimination half-life; T1/2k10: elimination half-life;
release of bile is assumed to occur as a bolus at the time of expulsion from the gall bladder (Ttom) into the
GI tract; D_rec: dose recovery from bile; AUC: area under the curve by the trapezoidal integral; AUMC:
area under moment curve by the trapezoidal integral; MRT: mean residence time
Parameter
Unit
Oral
ka
h-1
1.48 ± 0.41
k10
h-1
0.16 ± 0.05
k1g
h-1
0.11 ± 0.04
Ttom
h
6.14 ± 0.77
T1/2ka
h
0.47 ± 0.10
T1/2k1g
h
5.36 ± 0.52
T1/2k10
h
6.69 ± 0.67
D_rec
mg/kg
5.98 ± 0.71
D_rec/Dose
%
3.12 ± 0.08
Tmax
h
1.42 ± 0.34
Cmax
μg/ml
222.39 ± 20.22
AUC0-
g•h/ml
1596.61 ± 85.25
AUMC
g•h2/ml
7158.64 ± 214
MRT
h
8.48 ± 1.00
13
0.1
1
10
100
0.25 0.5 1 2 4 6
Serum concentrations µg/ml
Time (h)
Figure 2: Mean ± SD of serum concentrations of doxycycline in turkeys
after single intravenous, intramuscular and dosing of 20 mg/kg b.w.
(n=5)
I/V I/M oral
14
1
10
100
1000
10000
0.5 1 2 4 6
Cumulative bile concentration (µg/ml)
Time (h)
Figure 3: Mean ±SD of bile concentrations of doxycycline in turkeys
after single intramuscular and oral dosing of 20 mg/kg b.w. (n=5)
I/M Oral
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Awarded first prize in the Internal Medicine category of the British Medical Association Book of the Year Awards, 2012. Following a Tradition of Excellence. from reviews of previous editions: "the best source of synthesized clinical wisdom" -Gastroenterology "a tour de force in terms of knowledge and effort" -TheNew England Journal of Medicine "the foremost liver book in the world" -The Journal of the American Medical Association. "beautifully produced" -Hepatology Over the past 56 years, thousands of physicians have depended on Diseases of the Liver and Biliary System. Its didactic and reliable clinical guidance was - and still is - beyond comparison. This brand-new edition, now named Sherlock's Diseases of the Liver and Biliary System, after the late Professor Dame Sheila Sherlock, continues to provide concise clinical guidance for all those treating patients with hepato-biliary disease. Enabling clinicians to formulate incisive diagnoses and appropriate treatment strategies, this book has been updated to reflect the advances that have been made in the last 10 years, providing didactic and reliable clinical guidance in hepatology from the world's leading experts. A consistent chapter structure allows readers to access the information immediately, with summary boxes and key learning points throughout, and special emphasis on the latest in evidence-based clinical guidance. And for the first time, this edition now offers a free companion website providing the 680 full-color illustrations and figures in the book, for use in scientific presentations.
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