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Research Article
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Comparative Pharmacokinetics of Intramuscular Ceftriaxone Co-Administered with Acetaminophen in Healthy and Infected Sokoto Red Goats |
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Abdulgafar O. Jimoh,
Shaibu O. Bello,
Emmanuel U. Etuk,
Solomon A. Adeleye
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Vincent U. Igbokwe
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ABSTRACT
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This study was aimed at finding out if paracetamol influences the pharmacokinetics of ceftriaxone in healthy and salmonella thyphimurium infected Sokoto red goats. In a randomised three-way study, 15 healthy male goats weighing 10-13 kg were divided into three groups of five goats each and each group got either a single intramuscular dose of 1 g ceftriaxone only, 1 g ceftriaxone co-administered with 300 mg paracetamol or 1 g ceftriaxone co-administered with 300 mg paracetamol plus inoculation with Salmonella thyphimurium. Non compartmental Pharmacokinetic parameters were measured in plasma samples by microbiological assay. There was a statistically significant (p<0.01) decrease in the values of absorption half life (0.51±0.004, 0.17±0.02 and 0.14±0.03 h), maximum plasma concentration (Cmax) (45.6±0.19, 19±0.32 and 16.5±0.18 μg mL-1), area under the curve (AUC) (144.1±1.711, 42.24±2.11 and 27.50±0.68 μg/h/mL); and also a statistically significant (p<0.01) increase in the values of elimination half life (0.58±0.012, 5.34±1.85), Volume of Distribution (Vd) (485.3±15.725, 14382.8±4418.9 and 10467±954.83 mL kg-1) and Clearance (Cl) (578.8±6.880, 1992.72±101.89 and 3039.21±72.1 mL/h/kg) when pharmacokinetic parameters were compared for ceftriaxone alone and ceftriaxone co-administered with paracetamol in healthy and infected Sokoto red goats respectively. This study suggests that paracetamol and Salmonella thyphimurium infection alters the plasma disposition of ceftriaxone in healthy and infected Sokoto red goats. We concluded that paracetamol significantly influences the pharmacokinetic profile of ceftriaxone in healthy and infected Sokoto red goats, however further studies are required to confirm these findings and establish the mechanism(s) of interaction.
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How
to cite this article:
Abdulgafar O. Jimoh, Shaibu O. Bello, Emmanuel U. Etuk, Solomon A. Adeleye and Vincent U. Igbokwe, 2011. Comparative Pharmacokinetics of Intramuscular Ceftriaxone Co-Administered with Acetaminophen in Healthy and Infected Sokoto Red Goats. International Journal of Pharmacology, 7: 623-628. DOI: 10.3923/ijp.2011.623.628 URL: https://scialert.net/abstract/?doi=ijp.2011.623.628
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Received: April 04, 2011;
Accepted: June 08, 2011;
Published: July 23, 2011
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INTRODUCTION
The clinical consequences of drug interactions may be antagonistic, additive,
synergistic or idiosyncratic, resulting in treatment failure, increased pharmacologic
effect or toxic reactions. Pharmacokinetic drug interactions are a consequence
of altered levels of exposure to the drug or its metabolites through the alteration
of one or more of the pharmacokinetic processes. Monotherapy is desirable but
is rarely practicable, extra care should be taken when drugs whose pharmacokinetic
interactions are yet been ascertained are to be co-administered. It has been
advocated that co-administration of some drugs should be avoided or only in
situations where therapeutic drug monitoring can be performed (Pea
and Furlanut, 2001). It is essential to examine the influence of altered
physiology on the pharmacokinetics of drugs, especially when there are some
co-existing pathophysiological conditions affecting drug disposition (Ambros
et al., 2010). It is therefore, important to study and document the
pharmacokinetic outcome of drugs that could possibly be co-administered.
Ceftriaxone is a third generation cephalosporin that is widely used in bacterial
infections. Paracetamol is a para-aminophenol derivative also known as acetaminophen,
a routinely used non-narcotic analgesic, antipyretic agent widely used over
the counter for adults and children (Sharma and Srivastava,
1997). It is a common practice to co-administer analgesics and antipyretics
for fever and pain in patients receiving antibiotics for infections (Issa
et al., 2007). Studies have documented the Pharmacokinetic profile
of ceftriaxone when administered alone in different conditions (Tiwari
et al., 2009; Sar et al., 2006; Ismail,
2005), Influence of paracetamol and Salmonella thyphimurium infection
on the plasma kinetics of ceftriaxone in the Sokoto red goat has not been reported
to our knowledge. The Sokoto red goat is the most important goat breed in Nigeria,
accounting for about 70% of the estimated 34.5 million goats in Nigeria (Osuhor
et al., 1998), it is the predominant of the three breeds of goats
in Nigeria and the most widely used and distributed breed in the northern savannah
belts of the country (Ngere et al., 1984).
Thus, the purpose of this study was to compare the influence of paracetamol on the plasma kinetics of ceftriaxone in healthy and infected Sokoto Red Goats. MATERIALS AND METHODS Animals: Fifteen apparently healthy male Sokoto red goats weighing 10-13 kg were purchased from Dange market in Dange-Shuni Local Government Area of Sokoto State. The goats were housed separately in groups of five and conditioned in pens with concrete floors in the large animal unit of the Faculty of Veterinary Medicine, Usmanu Danfodiyo University Sokoto. They were fed on wheat bran, bean offal, cowpea hay, while water was provided ad libitum. Before the commencement of the experiment, the goats were examined and screened to ensure that they were in healthy condition. The animals were evaluated every 24 h after purchase during the period of acclimatization which lasted two weeks. Study design: The first group received 1 g ceftriaxone only, the second group received 1 g ceftriaxone plus 300 mg paracetamol, while the third group which are a pre-validated model of Salmonella thyphimurium infection also received 1 g of ceftriaxone plus 300 mg of paracetamol. All drugs were administered via the intramuscular route. Venous blood samples collected via the jugular vein (5 mL) were drawn pre-dose and at 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12, 24 and 48 h. The samples were collected in heparinized centrifuge tubes. All the samples were centrifuged, plasma separated and frozen until running the analysis. Drugs: Paracetamol injection containing 300 mg in 2 mL (PANAGREEN INJECTION) with batch number 93, nafdac registration number 04-8485, manufacturing license No. KTK/28A/445/2001, manufacturing date of February 2007 and expiry date of January 2010, manufactured by GVS LAB, 2, Swamigeha, Ursekarwadi, Dombivl i(E)-421201, India. Generic ceftriaxone injection containing 1 g ceftriaxone powder (PAN-CEFTRIAXONE) with lot/batch number B704128, with manufacturing date of April 2007 and expiry date of April 2010, manufactured by Panpharma Laboratories, Luitre-35133 Fougeres-France.
Inoculation of sokoto red goats with Salmonella typhimurium:
Stock culture of Salmonella typhimurium was used. Each of the ten goats
received orally a 10 mL suspension containing 2x109 organism mL-1.
The goats rectal temperature were recorded daily and signs of ill health noted
daily, including appearance, activity, feeding habits and bowel movement. Blood
was collected aseptically from the goats jugular veins for haematological
tests. Clinical features indicating infection were noted in the infected goats
(Otesile et al., 1990).
Pharmacokinetic analysis: Cetriaxone in plasma samples was determined
by microbiological assay using agar well diffusion method (Iroha
et al., 2008). Pharmacokinetic parameters were calculated by inputting
the concentration-time data obtained into the pharmacokinetic software PK Solution
2.0 and curve stripping was performed using the least-square technique (Zuluaga
et al., 2009).
Determination of the regression equation: Pooled plasma from Sokoto
red goats was used as diluents to constitute 2.5, 5, 10, 15, 20, 25, 30, 35,
40, 45 and 50 μg mL-1 Ceftriaxone solution. Using the agar well
dilution technique, the inhibition of the growth of Escherichia coli
was observed and measured using a vernier calliper. A regression equation Y
= ax+C and correlation co-efficient (R = 0.9935, p<0.0001) was then generated
from the concentration response curve using Graph pad instate software.
Statistical analysis: Data was expressed as Mean±SEM. The results were analysed using Graph Pad instate version 3 software and Students t-test was employed for comparing the means between groups. Differences were considered to be significant at p≤0.05. RESULTS
Co-administering ceftriaxone with paracetamol in both healthy and Salmonella
thyphimurium infected goats caused a fall in values of measured plasma ceftriaxone
concentration over time (Table 1).
Half life (t1/2): This is a measure of the rate of removal of drug from the body. It is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%. In other words, it is the time required to change the amount of drug in the body by one-half during elimination or during a constant infusion. The absorption half life (0.51±0.004, 0.17±0.02 and 0.14±0.03 h), was significantly (p=0.01) decreased, while the elimination half life (0.58±0.012, 5.34±1.85, 2.40±0.28), was increased when values were compared for ceftriaxone alone and ceftriaxone co-administered with paracetamol in healthy and infected Sokoto red goats, respectively. The increase in the elimination half life was only statistically significant (p<0.01) in the healthy goats (Table 2). Maximum plasma concentration (Cmax): This refers to the peak serum concentration attained by a therapeutic drug. There was a statistically significant (p<0.01) fall in the value of the Cmax (45.6±0.19, 19±0.32 and 16.5±0.18 μg mL-1) attained at a Tmax of 0.7±0.12, 0.5±0.00, 0.5±0.00 h, respectively, when values were compared for ceftriaxone alone and ceftriaxone co-administered with paracetamol in healthy and infected Sokoto red goats, respectively (Table 2).
Table 1: |
Plasma Ceftriaxone concentrations following a single intramuscular
injection alone and when co-administered with paracetamol in healthy and
salmonella thyphimurium infected Sokoto red goats |
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This table shows the mean concentrations±SEM against
time for all animals in the groups (n = 5) |
Minimum plasma concentration (Cmin): Also referred to as the trough serum concentration and is the point of minimum concentration of a drug or therapeutic agent in plasma, this occurs immediately before administering a drugs next dose. In this study the minimum measurable plasma concentration obtained at 6 h post drug administration in the three groups were 1.73+0.00, 0.80+0.10 and 0.66+0.03 μg mL-1 (Table 1). Area under the plasma concentration time curve (AUC): There was a significant (p<0.01) fall in the AUC (144.1±1.711, 42.24±2.11 and 27.50±0.68 μg/h/mL) when values were compared for the three groups (Table 2). Volume of distribution (Vd): This is a measure of the apparent space in the body available to contain the drug. It relates the amount of drug in the body to the concentration of drug (C) in blood or plasma. Our study revealed a significant (p<0.05) rise in the volume of distribution (485.3±15.725, 14382.8±4418.9 and 10467±954.83 mL kg-1) when values were compared amongst the three groups (Table 2). Clearance (CL): is a measure of the bodys efficiency in eliminating drug. Clearance of a drug is the ratio of the rate of elimination by all routes to the concentration of drug in a biologic fluid. There was a significant increase in the values obtained for clearance (578.8±6.880, 1992.72±101.89 and 3039.21±72.1 mL/h/kg) when pharmacokinetic parameters were compared for ceftriaxone alone and ceftriaxone co-administered with paracetamol in healthy and infected Sokoto red goats, respectively (Table 2). The plasma kinetic behavior of ceftriaxone when administered alone or when co-administered with paracetamol in healthy and infected Sokoto red goats after intramuscular injection could be best described by a one compartment open model with an absorption, distribution and elimination phase (Fig. 1-3).
Infecting the Sokoto red goats with Salmonella thyphimurium infection
resulted in a rise in rectal temperature, significant reduction in feed intake,
passage of frequent watery and offensive faeces and lethargy and a significant
rise in white blood cell count.
Table 2: |
Pharmacokinetic parameters of Ceftriaxone administered alone
and co-administered with paracetamol in healthy and infected Sokoto red
goats |
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This table shows mean pharmacokinetic parameters±SEM
for all animals in the groups (n = 5). *Significant (p<0.05), **Not significant
(p>0.05) |
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Fig. 1: |
Semi-Log of concentration-time curve of ceftriaxone following
a single intramuscular administration in healthy Sokoto red goats |
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Fig. 2: |
Semi-Log Plot of concentration-time curve for ceftriaxone
plus paracetamol in healthy Sokoto red goats |
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Fig. 3: |
Semi-Log of concentration-time curve of ceftriaxone following
a single intramuscular administration co-administered with paracetamol in
infected Sokoto red goats |
DISCUSSION
The influence of paracetamol on the pharmacokinetics of ceftriaxone in healthy
and infected Sokoto red goats was examined in this study. Intramuscular pharmacokinetics
of ceftriaxone was investigated in healthy goats after administration of 1 g
ceftriaxone. The kinetic behavior of ceftriaxone in healthy goats followed the
one compartment open model; the plasma concentration-time curve of ceftriaxone
was triphasic with an absorption, distribution and elimination phase. Peak plasma
concentration (Cmax) of 45.6±0.19 μg mL-1 was observed
at (Tmax) 0.7±0.12 h following intramuscular administration in healthy
Sokoto red goats. Similar previous studies also reported Cmax in calves, goats
and sheeps (20.3±0.92 mg mL-1) (23.6±1.2 mg mL-1)
and (23.16±2.94 mg mL-1), respectively (Srivastava
and Johal, 1998; Ismail, 2005; Goudah
et al., 2006). Following intramuscular administration in healthy
goats, t he elimination half-life (0.58±0.012 h), AUC (144.1±1.71
μg/h/mL) of ceftriaxone was reported.
The pharmacokinetic parameters of ceftriaxone given alone and in combination
with paracetamol in healthy and infected Sokoto red goats reveals that paracetamol
and Salmonella thyphimurium significantly influenced ceftriaxone plasma
kinetic behavior, as evidenced in Table 2. In a similar study
it was revealed that pharmacokinetics of ceftizoxime was altered by concomitant
administration of paracetamol in cross-bred calves (Singh
et al., 2008). Co-administration of Paracetamol and ciprofloxacin
was also reported to cause an increased concentration-time profile of Ciprofloxacin
(Issa et al., 2007). It was also observed in
calves wherein paracetamol was found to increase the AUC of levofloxacin on
concurrent administration (Dumka, 2007). Paracetamol
has been shown to increase the elimination half-life of oxytetracycline in goats
(Manna et al., 1993). The co-administration of
non steroidal anti inflammatory drugs with cephalosporins has been associated
with pharmacokinetic interactions (Chaudhary and Srivastava,
1999). Paracetamol has also been reported to alter the disposition of cephalosporins
(Sharma and Srivastava, 1997), findings in the above
mentioned studies support our suggestion that paracetamol significantly influence
the pharmacokinetics of ceftriaxone in Sokoto red goats. Speculation concerning
the mechanism of interaction between analgesics and antimicrobials has focused
on drug absorption, distribution, metabolism and elimination. Several drugs
are known to alter the hepatic metabolism of other drugs by enzyme induction
or inhibition. NSAIDs are known to precipitate renal failure in hepatic disease
(Mazoit et al., 1987) and inhibit renal production
of prostaglandins eventually leading to renal dysfunctions (Rossat
et al., 1999). Portal hypertension may lead to low peripheral resistance
and hyperdynamic circulation due to increased production of vasodilating substances
such as nitric oxide (Martin et al., 1998). The
observed effect of paracetamol on the pharmacokinetics of ceftriaxone may be
due to alteration in the rate of drug elimination from body.
In similar studies, infections have been shown to alter the plasma disposition
of some drugs (Etuk and Onyeyili, 2006; Burrows
et al., 1986; Groothuis et al., 1979),
these are in support of our suggestion that Salmonella thyphimurium infection
in Sokoto red goats significantly alters the plasma kinetics of ceftriaxone.
These alterations may be due to fever and inflammation induced by the infection.
Fever and inflammation occurring in infection may cause an increase in heart
rate and cardiac output, increasing blood flow to the liver and kidneys, all
these could lead to increase in the rate at which the drug is delivered to both
organs which are important sites of drug excretion (Etuk
and Onyeyili, 2006).
CONCLUSION This study suggests that paracetamol and Salmonella thyphimurium infection alters the plasma disposition of ceftriaxone in healthy and infected Sokoto red goats. This may imply that a dose adjustment may be necessary when co administering ceftriaxone and paracetamol in healthy and infected Sokoto red goats. The mechanisms of interaction were not studied. Further studies are needed to confirm these findings and establish the mechanism of interaction.
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