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Journal of Veterinary Medicine. A, Physiology, Pathology, Clinical Medicine, 2000, Feb, 47(1), 37-41

Pharmacokinetics of  Miocamycin  Following Intravenous  Administration to Cattle

N. J. Litterio, M. R. Rubio, E. A. Formentini, D. C. Díaz, E. J. Picco, T. Encinas and J. C. Boggio

ABSTRACT

The plasma pharmacokinetics for a single intravenous dose (10 mg/kg body weight) of miocamycin (a 16-membered macrolide drug) was investigated in Holando Argentino cattle (n = 5). Blood drug concentrations were determined by a microbiological method and data were best-fitted to a two-compartment open model. The pharmacokinetic profile consisted of a short distribution phase (t _1/2  = 7.41 ± 0.53 min), followed by an extended terminal elimination phase (t _1/2  = 2.49 ± 0.23 h). The volume of distribution at steady-state was large (2.13 ± 0.17 l/kg), suggesting extensive tissue distribution, the clearance value was 0.60 ± 0.03 l/h.

INTRODUCTION

Miocamycin is a 16-membered macrolide anti-microbial drug with bactericidal or bacteriostatic effects depending on dose. Miocamycin is effective against Gram-positive and Gram-negative organisms, atypical microbes and some anaerobes, it is similar to erythromycin with differences in potency between the two drugs for particular organisms. Miocamycin is inactive against Enterobacteriaceae, possesses poor activity against Haemophilus influenzae but is active against erythromycin-resistant staphylococcal and streptococcal species expressing inducible-type resistance ( Felminghan et al. 1991).

The anti-microbial activity of the drug has been attributed to inhibition of RNA-dependent protein synthesis. Miocamycin inhibits the enzymes responsible for the cellular fission septum; it provokes cell wall thickening and consequently prevents bacterial replication ( Casella 1992). It has been demonstrated in vitro that miocamycin induces increases in leukotriene B₄ production in polymorphonuclear cells, chemotaxis, killing of Candida albicans and respiratory burst, and the response varies according to the concentration of the antibiotic. Miocamycin presents post-antibiotic effect; it is able to show continued inhibition of bacterial regrowth after withdrawal of short-term exposure to an anti-microbial agent in vitro. This phenomenon may be of clinical relevance when blood and tissue drug concentrations fall below effective levels during intervals between drug administrations ( Okubo et al. 1995).

The pharmacokinetic behaviour of different macrolide drugs has been studied in various animal species. In human beings, macrolides (including miocamycin) are the primary drugs of choice for a number of clinically significant infections in children (pharyngitis, otitis, pneumonia, skin infections) ( Adam 1992). In human beings, it has been demonstrated that penetration of miocamycin into body tissues and fluids is both rapid and extensive, and its three major metabolites (Mb6, Mb12 and Mb9a) possess anti-microbial activity and may contribute to the therapeutic efficacy of the drug ( Nicoletti et al. 1983).

Although miocamycin (as well as other macrolide antibiotics) could be very useful in veterinary medicine, especially for the treatment of bovine respiratory disease, further confirmation and study of various aspects of its efficacy, tolerability and kinetic disposition, are needed before considering miocamycin as a useful alternative oral therapy to erythromycin for the treatment of respiratory tract and urogenital infections in ruminant species due to the fact that information on the disposition kinetics of miocamycin in these species is limited ( Holliday & Faulds 1993).

The purpose of this study was to describe the pharmacokinetic behaviour of miocamycin following administration to cattle by intravenous injection of a single dose.

MATERIALS AND METHODS

Five male Holando Argentino cattle (85-120 kg body weight and 4.5-6 months old) were used. All animals were clinically examined to ensure that they were healthy before the start of the study. Animals were housed in individual pens and given mixed rations and water ad libitum throughout the period of study. Just before the trials began, in-dwelling venous catheters were placed.

A single 10 mg/kg bolus injection of miocamycin (100 mg/ml, propyleneglycol : water, 60 : 40) was administered intravenously in the right jugular vein. During and after the drug administration the calves were observed for signs of local and systemic toxicity. In each animal, whole-blood samples were taken from an indwelling venous catheter into heparin tubes at 0, 5, 10, 15, 20, 30 and 45 min and 1, 2, 4, 8, 10 and 24 h after drug administration. Serum was separated by centrifugation (2000 g for 20 min) and stored at 20°C until drug analysis was performed within 7 days.

Miocamycin concentrations were determined using a microbiological method. The test organism was Sarcina lutea ATCC 9341 and the culture medium was Mueller Hinton agar ( Arret et al. 1971). A linear calculation curve of standard miocamycin (0.2-25.0 g/ml.) was obtained. The limit of quantification of this technique was 0.048 g/ml and the coefficients of variation inter- and intra-assay were below 10 %.

The concentration of drug versus time curves for each individual animal were analysed using the PKCALC computer program ( Shumaker 1986) by a least-squares regression analysis. Selection of the compartmental pharmacokinetic model that best fitted the data was based on the Pearson correlation coefficient (R) and Akaike's information criterion (AIC).

The AUC_0t was determined by using the linear trapezoidal rule. The pharmacokinetic parameters were estimated for each individual animal and reported as the mean of five animals ± standard deviation.

RESULTS

The mean serum of miocamycin concentration-time curve for intravenous administration is presented in Fig. 1 and listed in Table 1. The disposition kinetics of miocamycin given intravenously were best described by the following biexponential equation:

where Cp is the miocamycin plasma concentration at time t.

Therefore, the data for miocamycin following intravenous administration were best fitted according to a two-compartment model with an elimination rate of 0.29 h ¹ (t _1/2  = 2.49 ± 0.23 h) and volume of distribution at steady-state of 2.13 ± 0.17 l/kg ( Table 2).

FIGURES

Fig. 1 Mean miocamycin concentrations in plasma versus time following intravenous administration of mi...

Table 1 Plasma concentrations versus time of miocamycin in cattle after intravenous (10 mg/kg) administ...

Table 2 Pharmacokinetic parameters of miocamycin after single intravenous administration (10 mg/kg) to ...

DISCUSSION

The pharmacokinetics of miocamycin after intravenous (10 mg/kg) administration to sheep, as well as those reported in various domestic animals ( Nicoletti et al. 1983; Furneri et al. 1988; Holliday & Faulds 1993) have been best described using a two-compartment model.

The microbiological assay is indicative of any anti-bacterial activity that is representative of miocamycin, as well as any active metabolites of miocamycin concentrations in the samples. As blank plasma did not yield any zones of inhibition, it is safe to assume that the observed anti-microbial activity in the samples is a result of miocamycin administration. For these reasons, the miocamycin concentrations determined using the microbiological assay should be interpreted as miocamycin equivalent activity.

The miocamycin equivalent activity remained above the minimum effective concentration for Clostridium spp., Listeria spp. and Bacteroides fragilis (3.13 g/ml) ( Casella 1992; Holliday & Faulds 1993) for 45 min, and for the majority of the sensitive micro-organisms (1 g/ml) ( Felminghan et al. 1991) for 4 h.

The distribution half-life was shorter (7.41 ± 0.53 min) but the elimination half-life of miocamycin in cattle (2.49 ± 0.23 h) was longer in the present study (by microbiological assay) than that reported for humans (0.98 h) after oral administration (by high performance liquid chromatography) ( Holliday & Faulds 1993). This may be because miocamycin equivalent activity persists much longer compared to the activity of the parent compound. This observation is consistent with the previously reported longer half-lives of Mb6 (2.34 h) and Mb9a (2.10 h), the major active metabolites of miocamycin, compared to miocamycin ( Nicoletti et al. 1983).

The volume of distribution at steady-state (Vd_ss) was large (2.13 l/kg), suggesting extensive tissue distribution, as occurs with miocamycin (3.26-4.7 l/kg) ( Fioretti et al. 1984; Nicoletti et al. 1983) and with other macrolides in human beings. Large volumes of distribution usually indicate that the amount of the drug in plasma is very small. So, the volume of the central compartment (0.52 ± 0.03 l/kg) is low and the volume at steady-state is large (2.13 l/kg). These data confirm that miocamycin and its metabolites were extensively distributed extravascularly. The difference between rate constants K₁₂ and K₂₁ (K₁₂ : K₂₁ = 2.17) indicates that once in the tissues, the drug moved back into the blood slower than it penetrated. Consequently, tissue drug residues may remain high for a period of time. This high tissue concentration has been proved for miocamycin in other animal species, and tissue to plasma concentration ratios exceeding 100 % for oral cavity, respiratory and urogenital tracts, and about 600 % for bronchial secretions have been reported ( Fioretti et al. 1984; Furneri et al. 1988). The high tissue concentration has been attributed to the physiochemical properties (lipophilicity, charge and pKa) of the macrolide antibiotics. They are weak organic bases that result in ion trapping and accumulation in the intracellular fluid.

The combination of the post-antibiotic effect, previously demonstrated for macrolide antibiotics ( Okubo et al. 1995), and the extensive tissue distribution of the active metabolites, may prolonge the pharmacological effect of miocamycin in spite of the short elimination half-life of the parent drug.

REFERENCES

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•    Arret, B., D. P. Johnson, A. Kirstbaum 1971 Outline of details for microbiological assay of antibiotics: second revision. J. Pharm. Sci. , 60, 1689 1694.

•    Casella, J. 1992 Actividad antimicrobiana de la miocamicina. In: Stamboulian, D. & N. González Sandaña, eds. Simposio Internacional Sobre Nuevos Macrólidos: Rol de la Miocamicina, pp. 10 12. Fundación del Centro de Estudios Infectológicos, Buenos Aires.

•    Felminghan, D., J. J. Robbins, M. Sanghrajka, A. Leakey, R. G. Ridgway 1991 The in vitro activity of some 14-, 15- and 16-membered macrolides against Staphylococcus spp., Legionella spp., Mycoplasma spp. & Ureaplasma urealyticum . Drugs Exp. Clin. Res. , 17, 91 99.

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•    Furneri, P. M., G. Scalia, A. Garozzo, G. Tempera 1988 Some pharmacokinetic data on miocamycin I. Serum, urinary and prostatic levels. Drugs Exp. Clin. Res. , 14, 755 762.

•    Holliday, S. M. & D. Faulds 1993 Miocamycin: a review of its antimicrobial activity, pharmacokinetics properties and therapeutic potential. Drugs, 46, 720 745.

•    Nicoletti, P., M. Rizzo, T. Mazzei, A. Novelli, M. Ciuffi 1983 Aspectti farmacocinetici della miocamicina. Ital. Chemioter. 2 (Suppl.) , 3), 140 141.

•    Okubo, T., T. Suzuki, K. Fujita, S. Iyobe, M. Inoue 1995 Postantibiotic effects (PAE's) of macrolide antibiotics evaluated using Bioscreen C method. JPN. J. Antibiot. , 48, 458 462.

•    Shumaker, R. C. 1986 PKCALC: a basic interactiva computers program for statistical and pharmacokinetic analysis of data. Drug Metab. , 17, 331 348.

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