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Alteration of pharmacokinetics of oxytetracycline following oral administration of Piper longum in hens

The pharmacokinetic profile of orally administered oxytetracycline (10 mg/kg body weight) was studied 7 days post oral treatment of Piper longum (15 mg equivalent/kg) in White Leghorn hens (2-2.8 kg). On the day 8, oxytetracycline (OTC) was administered orally and blood samples were collected from the wing vein in heparinised vials for plasma separation at 0 (pre-treatment), 15, 30, 60, 120, 240, 360, 480 and 600 minutes post OTC administration. Plasma OTC concentrations were determined by microbial assay technique using Bacillus cereus var. mycoides (ATCC 11778) as test organism. The plasma levels of OTC against time were adequately described by one compartment open model. The pharmacokinetic data revealed that P. longum treated animals had significantly higher area under curve (AUC), area under the first moment of plasma drug concentration-time curve (AUMC) and mean residential time (MRT). Prior treatment of P. longum significantly reduced elimination rate constant (β) and increased elimination half life (t½β). The total body clearance (ClB) reduced by 21% whereas total duration of pharmacological effect (td) increased by 29%. The treatment with P. longum reduced loading and maintenance dose by 33.3 and 39%, respectively.

Key words: oral administration, oxytetracycline, pharmacokinetics, Piper longum, white Leghorn.

Introduction

Oxytetracycline has wide scope in the treatment of various bacterial, rickettsial and mycoplasmal infections of poultry and other avian species. Notwithstanding its broad spectrum of activity, its therapeutic effectiveness is marred by its poor bioavailability by oral route [6]. Absorption of tetracyclines mostly takes place from stomach and upper part of small intestine. Most of the tetracyclines are incompletely and irregularly absorbed from gastrointestinal tract and only a small proportion of administered dose appears in the circulating blood and tissue at any given time [19]. Long pepper (Piper longum) is widely used in the Indian System of Medicine (Ayurvedic System) along with black piper and ginger to enhance the therapeutic efficacy of the concurrently administered drugs. The pretreatment of P. longum has been reported to increase the rate and extent of absorption of some of the drugs widely used in human medicine which are moderately absorbed on their own by enhancement of blood supply through vasodilatation [1,4], inhibition of their metabolism [5] or inhibition of renal clearance [5]. The present studies were therefore, undertaken to study whether P. longum pretreatment enhances the bioavailability of oxytetracycline administered orally in white Leghorn hens.

Materials and Methods

The study was conducted on poultry birds divided into two groups with 8 birds in each group weighing 2-2.8 kg. They were kept under close observation for one week before the commencement of experiment to enable them to acclimatize in the new environment. They were housed on deep litter and were fed an antibiotic free diet. Feed and water were provided ad libitum. The birds in Group I were administered oxytetracycline (Terramycin; Pfizer, India) orally at the dose rate of 10 mg/kg. The birds in Group II were fed P. longum at the dose rate of 15 mg piperine equivalent per kg/body wt for seven days. On day 8, oxytetracycline was administered orally as in Group I. Blood samples of the animals of both the groups were collected from the wing vein in heparinized vials at time intervals of 0, 15, 30, 60, 120, 240, 360, 480 and 600 min.

The blood samples collected were centrifuged at 3,000 rpm for 10 minutes for plasma separation. The samples were frozen at −20o C till assayed. P. longum was standardized for the presence of piperine content in it by spectrophotometric method developed at Research and Development Laboratory, Indian Herbs, Saharanpur [8]. The concentration of oxytetracycline in plasma was determined by using microbial assay technique using Bacillus cereus var mycoides (ATCC 11778) as the test microorganism [2]. The plasma concentration-time profile of oxytetracycline for each bird was used to determine its pharmacokinetics. Different pharmacokinetic parameters were analyzed using “method of least square” and “method of residual yields” as described by Gibaldi and Perrier [9]. The plasma concentration-time profile of oxytetracycline of each animal was used to determine pharmacokinetics. Estimation of the areas under the concentration-time curve (AUC) and the area under the first moment of plasma drug concentration-time curve (AUMC) were based on trapezoidal rule [9]. The compartmental analysis was done using the mono-exponential equation: Cp(t) = Be-β.t – Ae-ka.t, where Cp is the plasma drug concentration, B is the zero time intercept of regression line of elimination phase, A is the zero time plasma drug concentration intercept of regression line of absorption phase, Ka is the absorption rate constant, β is the overall elimination rate constant, t is the time and e is the natural logarithm base. The dosage regimen for maintaining MIC of 0.5, 1, 2, 3 and 4 µg/ml at the dosage interval of 6, 8 and 12 h was derived as per the method mentioned by Notari [12].

Results

The results of the study revealed that mean plasma concentration of oxytetracycline were significantly higher in P. longum treated birds during its entire absorption phase (Table 1, Fig. 1). The absorption rate constant and absorption half life, however, revealed a non significant change (p > 0.05). Further, findings of the present study indicated that prior administration of P. longum modified the kinetic profile of oxytetracycline (Table 2) as evidenced by higher area under curve (AUC), area under the first moment of plasma drug concentration time curve (AUMC), mean residence time (MRT) and total duration of pharmacological action (td). Prior administration of P. longum significantly reduced the elimination rate constant (β) and subsequently increased the plasma half life of oxytetracycline (Table 2). Total body clearance also confirmed a similar trend in P. longum treated birds. There was significant reduction (p < 0.01) of about 21% in total body clearance as compared to control birds. Computation of loading and maintenance dose revealed that prior treatment of P. longum reduced both loading and maintenance dose upto the extent of 33.26 and 39.0%, respectively at different minimum inhibitory concentrations of oxytetracycline (Table 3).

Discussion

Oxytetracycline has high bacteriostatic activity against a wide range of gram positive and gram negative microorganisms and is being effectively and successfully employed in the treatment of many bacterial infections in man and animals [14,15,18]. Absorption of oxytetracycline from gastrointestinal tract has been found to be inadequate and irregular. Only 60 % of the oral dose is absorbed. Antibiotic levels in blood and target organ directly affect the therapeutic efficacy of antibiotics. Piperine, an amide alkaloid isolated from different species of Piper has been reported to enhance the bioavailability of co-administered drugs [4,7,11,22]. So the study was undertaken to observe the effect of piperine on the pharmacokinetics of oxytetracycline.

The experimental data of observed plasma concentrations revealed that pharmacokinetics of oxytetracycline in poultry birds by oral route was adequately described by one compartment open model. This model has also been used by various workers to describe the pharmacokinetics of oxytetracycline after extravascular administration in various animals [13,20]. The findings of the present study further revealed that mean plasma concentrations of oxytetracycline were higher in P. longum treated birds during its entire absorption phase. The increased plasma concentration of oxytetracycline during absorption could be due to enhanced blood supply in enteric vessels as a result of local vasodilatation [1,3]. The higher values of AUC, AUMC and MRT in piperine treated birds were indicative of enhanced systemic availability of oxytetracycline and suppression of drug metabolizing activities. Piperine, the active principle of P. longum has been shown to inhibit drug metabolizing activities [17]. Besides, piperine treatment has been shown to enhance blood levels of many chemotherapeutic agents including sulphadiazine, pyrazinamide, rifampin, isoniazid in human volunteers [21]. Piperine treatment has also been known to increase plasma levels of nimesulide [11] and indomethacin [10]. A reduction in the loading and maintenance dose clearly indicates interactive pharmacokinetics action of P. longum and oxytetracycline. It is, therefore, imperative to assume that prior administration of P. longum increases total duration of antimicrobial action and subsequently enhances therapeutic efficacy of oxytetracycline in poultry birds. The reduction in loading and maintenance dose will be of immense economic significance. This would also reduce the subsequent side-effects as lesser amount of drug would be required to achieve desirable therapeutic efficacy.

Acknowledgments

We express our thanks to the Dean, College of Veterinary & Animal Sciences, CSKHPKV, Palampur, for providing necessary facilities to carry out the present investigation.

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Post time: Jun-30-2020
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