Pharmacokinetic and Residue Studies of Quinolone Compounds and Olaquindox in Poultry a Anadón, Mr Martinez-Larrañaga, Mj Diaz, C Velez, P Bringas

Home , Enoxacin, Flumequine, Nalidixic acid, Oxolinic acid, Pipemidic acid, Piromidic acid

Pharmacokinetic and residue studies of quinolone compounds and olaquindox in poultry A Anadón, Mr Martinez-Larrañaga, Mj Diaz, C Velez, P Bringas

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A Anadón, Mr Martinez-Larrañaga, Mj Diaz, C Velez, P Bringas. Pharmacokinetic and residue studies of quinolone compounds and olaquindox in poultry. Annales de Recherches Vétérinaires, INRA Editions, 1990, 21 (suppl1), pp.137s-144s. hal-00902002

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A Anadón MR Martinez-Larrañaga MJ Diaz, C Velez P Bringas

Department of Pharmacology, Institute of Pharmacology and Toxicology, CSIC, Faculty of Medicine, Complutense University, 28040 Madrid, Spain (Pharmacokinetics of Veterinary Drugs, 11-12 October 1989, Fougeres, France)

Summary ― Nalidixic acid and similar antimicrobial agents have been available for more than 20 years, mainly for treating infections caused by Gram-negative enterobacteria. Recently, several chemically related drugs, including oxolinic acid, pipemidic acid, piromidic acid and flumequine, have been developed. They are either naphthyridine-carboxylic acid or quinoline!arboxylic acid deriva- tives and, with nalidixic acid, are so-called quinolones. A major advance in antimicrobial chemotherapy was the synthesis of newer quinolones containing at least 1 fluorine atom and a piperazinyl group. These new fluoroquinolones have an extended antimicrobial spectrum compared to the first quinolone generation, and are highly active against most Gram-negative pathogens including the Enterobacteriaceae and Pseudomonas aeruginosa. The pharmacokinetic properties and residue levels of these quinolones and fluoroquinolones for which clinical experience or experimental information exists in poultry are reviewed here. On the other hand, administration of the quinoxaline-di-11! oxide, olaquindox, for medical purposes raises questions concerning the pharmacokinetic disposition of the drug and the risk of its residues in poultry. This paper presents information about the pharmacokinetic profile of olaquindox and the presence of its residues in chickens. quinolone / poultry / pharmacokinetics / residues

Résumé ― Étude pharmacocinétique des quinolones et de l’olaquindox chez la volaille. L’acide nalidixique et ses analogues structuraux sont utilisés dans le traitement des infections cau- sées par des entérobactéries Gram négatif. Ces dernières années, des médicaments chimiquement voisins ont été développés : acide oxolinique, acide pipémidique, acide piromidique et fluméquine. Ces agents, appelés collectivement quinolones, dérivent de l’acide carboxylique-naphtyridine, de l’acide carboxylique-quinoline ou de l’acide nalidixique. Un progrès dans la chimiothérapie antimicro- bienne a été réalisé avec la synthèse de nouvelles quinolones contenant au moins un atome de fluor et un groupe pipérazinyle. Ces fluoroquinolones ont un plus large spectre d action antimicrobi- en; elles sont très actives sur la plupart des agents pathogènes à Gram négatif notamment les En- terobacteriaceae et Pseudomonas aeruginosa. Les propriétés pharmacocinétiques et les niveaux des résidus liés à l’utilisation des quinolones et fluoroquinolones, chez la volaille, sont présentées dans ce travail. Une attention particulière a été portée à l’olaquindox. quinolone / volaille / pharmacocinétique l résidus INTRODUCTION STRUCTURE OF (!UINOLONES

Among oral anti-bacterial agents, the qui- The general structures of two of the most nolone class has been demonstrated to be studied classes of quinolones are shown in effective in the treatment of Escherichia figure 1. Molecular modifications of the coli infections in poultry, especially coliba- parent structures have been carried out in cillosis in broilers. Nalidixic acid (a 1,8- order to develop agents with higher poten- naphthyridine derivative), the first agent in cy and broader bacterial spectra. The re- this series, and a number of other chemi- sults of structure-activity studies per- cally related drugs (oxolinic acid, pipemidic formed to date can be summarized as acid, piromidic acid, flumequine), are ac- follows: maximum in vitro potency (ex- tive in vitro against a wide range of Gram- pressed as MICS) and in vivo efficacy oc- negative bacilli (with the exception of cur with a fluorine substituent at C-6 with Pseudomonas aeruginosa) but inactive the concomitant presence of an amino against Gram-positive organisms. In addi- functionality of optimal size at C-7 (fig 2). tion, the clinical use of first generation Fortunately, information on the dissocia- quinolones is often associated with the tion, solubility and solubility-pH relation- rapid emergence of resistant mutants ship for nalidixic acid, a model for the new- of new flu- (Fass, 1985). The development er quinolones, is available in the literature oroquine agents (norfloxacin, enoxacin, (Grubb, 1979; Staroscik and Sulkowska, ciprofloxacin, ofloxacin, enrofloxacin, 1971; Sulkowska and Staroscik, 1975). pefloxacin) with good systemic bioavaila- Nalidixic acid has two pKas which have bility and improved intrinsic antimicrobial been determined spectrophotometrically activity especially against P aeruginosa and Gram-positive organisms, has re- newed interest in this class of antimicrobial agents. The primary target of nalidixic acid and oxolinic acid and probably all the other fluoroquinolones is DNA gyrase (topoisomer- ase II), an essential bacterial enzyme that maintains superhelical twists in DNA (Coz- zarelli, 1980; Drlica, 1984; Gellert, 1981). The theoretical advantage of fluoroquinolones led to the evaluation of their pharmacokinetic parameters in poultry and to assess their therapeutic potential and their residue levels in food-producing animals. The encouraging results obtained in the preliminary trials prompted us to review these agents. Other quinoxaline-di-N- oxide compounds, such as olaquindox, will also be discussed. The use of this drug in poultry for medical purpose (anti-bacterial activity) may or r,,ay not have a practical relevance. (Staroscik and Sulkowska, 1971) by solubility measurements (Sulkowska and Sta- roscik, 1975) and by partition studies (Grubb, 1979). The spectrophotometric pKai of 0.94 corresponds to the dissociation of a protonated heterocyclic nitrogen of nalidixic acid, while the spectrophotometric pK! value of 6.02 corresponds to the dissociation of the carboxylic acid group (Staroscik and Sulkowska, 1971).). The dissociation scheme for nalidixic acid is given in figure 3. Their solubility-pH and partition-pH profiles have also been studied by Ogata et al (1984a) and Ismail and Gadalla (1983). The pkas determined by solubility were 1.03 ± 0.13 and 6.12 ± 0.03, whereas those determined by partition measurements were 0.86 ± 0.07 and 5.99 ± 0.03, respectively. In its neutral form (NH°), between pH values of 2 and 5, nalidixic acid has a solubility of 8.3 x 1Q-6 M (19 xg/ml) (Staroscik and Sulkowska, 1971). Most of the new quinolones have dissociation constants for their carboxyl group which are very similar to that of nalidixic acid. Substitution at the 7-position ap- the structure of olaquindox are given in pears to have little electronic or steric ef- figure 4. fect on the dissociation of the carboxyl group. In contrast to nalidixic acid, the new quinolone antimicrobials have a basic PHARMACOKINETICS functional group in the 7-position which has a much higher than the pKa heterocy- The pharmacokinetic characteristics of 7 clic nitrogen. This has a profound effect on agents are shown in table I. After oral ad- their solubility and partitioning properties ministration, these agents are more or less which in turn significantly influence their rapidly absorbed with con- and peak plasma pharmacological biopharmacological centrations reached within 3 h. Piromidic properties. The pKa values of several quin- acid, ciprofloxacin and are the olone antimicrobials have been deter- olaquindox most rapidly absorbed, reaching a maxi- mined (Ogata et al, 1984a, It b). appears mum level (Tmax) after 0.19 - 0.22 h follow- that the to the pKa corresponding carboxyl- ing administration. Norfloxacin is absorbed ic group is around 6.0 ± 0.3 and is relative- more slowly (Tmax 0.30 h), but enrofloxa- ly of substitution at the 7- independent cin, flumequine and oxolinic acid have the position. On the other the basic hand, slowest rates of absorption with Tmax of 1- amine can between 5 and pKa vary 9, de- 2, 2 and 2.72 h, respectively. The peak upon the chemical nature of the pending plasma levels reached are also dif- side chain. (Cmax) ferent and dose-dependent. Single oral The structures of the six quinolones doses of each of the 7 drugs considered in considered in the present report and the present review are able to reach peak plasma levels above 1 xg/ml (and thus that we observed in chickens are not in above the MIC for many organisms). The agreement with values reported by Sheer differences in Cmax values among different (1987) for enrofloxacin. These differences agents probably reflect variability in gas- may result from the use of different analyti- trointestinal When absorption. given orally cal methods (microbiological assay for en- at an equivalent dose, ciprofloxacin pro- rofloxacin vs HPLC assay for norfloxacin duces higher values of Cm! and of the and ciprofloxacin). area under the curve (AUC) of the plasma level plotted versus time (AUC is related to The of bioavailability). Cmax 3.54 !g/ml fol- RESIDUE LEVELS lowing the administration of 8 mg/kg of ciprofloxacin is higher than that observed for the same dose of norfloxacin (1.95 !g/ml). Few studies of tissue distribution and resi- The drugs considered, with the exception due levels of quinolone and quinoxaline of enrofloxacin, persisted in the body of compounds in poultry have been reported. chickens for a long time. The mean termi- Table II summarizes the available results nal plasma elimination half-life (t!!2! was (Anad6n et al, unpublished data). In poul- 5.13 h for olaquindox, 8 h for flumequine, try, the quinolone, oxolinic acid, piromidic 9.13 h for ciprofloxacin, 11.21 h for piro- acid and the quinoxaline compound, ola- midic 13.06 h acid, for norfloxacin and quindox, were widely distributed through- 33.54 for oxolinic acid. The mean of t1l2/3 out the body with tissue concentrations ex- enrofloxacin is about 2-3.5 h. ceeding 1 xg/ml 24 h after administration The relatively long plasma elimination (table II). This good tissue penetration and half-lives of norfloxacin and ciprofloxacin high drug concentrations well above the MIC for most bacterial pathogens (Barry, has been reported (Sheer, 1987). After a 1989) suggest the potential clinical use to single oral dose of 10 mg/kg to chickens, distrib- treat bacterial infections in poultry. In most enrofloxacin was rapidly and widely species of Enterobacteriaceae, nalidixic uted to tissues. Concentrations above 1 acid and pipemidic acid have similar activi- !g/g were found 4-6 h after drug adminis- ties (median MICs of 1.0-4.0 xg/ml); piro- tration in lung, heart, liver, spleen, kidney midic acid is less active against Gram- and muscle. However, the drug was also negative bacteria (median MICs of 1.0-100 eliminated quickly from tissues. Twenty- ,ug/ml). The first compound in the quino- four hours after drug administration, the fell below lone series (oxolinic acid) is much more ac- residue levels of enrofloxacin tive; the median MICs for different species 0.02-0.05 !g/g of tissue. This indicates duration of the antimicrobial effect are <0.5 J19/ml. Norfloxacin is 10-100- that the the time times more active than nalidixic acid. Other is shorter, since it depends upon free concentration fluoroquinolones are also extremely active during which the drug against the enteric bacilli; ciprofloxacin is exceeds the MIC of susceptible pathogens the most potent quinolone reported (Barry, (Baggot, 1980). 1989). Among various quinoxaline-1,4-di- N-oxides synthesized to date, the growth promoter olaquindox is also used in the CONCLUSIONS treatment and prevention of infectious dis- eases caused diverse bacteria, such as by The common pharmacokinetic properties E coli Salmonella and (Bertschinger, 1976) of the quinolones are: 1) a rapid oral ab- MICs of 8-16 (median 6 xg/ml) . sorption, 2) attainable serum and tissue However, on the basis of detected resi- concentrations above the MIC for most due levels, specific requirements might in- Gram-negative and many Gram-positive clude a preslaughter withdrawal time. As- organisms, and 3) relatively long half-lives says of drug concentrations in muscle, in plasma, allowing dose intervals of at liver and kidney showed that oxolinic acid, least 12 h. These features suggest possi- pipemidic acid and olaquindox persisted ble clinical applications. for a time in the of chickens. 01- long body Although many investigations remain to slowest aquindox was found to be the drug be done, since olaquindox persists in the eliminated from the body with an un- body of chickens for at least 14 d, this drug concentration of 0.03, 0.11l changed drug may pose a toxicological risk for man if a and 0.12 Ji9/g of muscle, liver and kidney preslaughter withdrawal time is not ob- 14 d after oral tissues, respectively, drug served. Currently, available data on oxolin- administration. ic acid and piromidic acid residues recom- No data have yet been published on the mend a preslaughter withdrawal time of tissue penetration of new fluoroquinolones 8 d. (norfloxacin, ciprofloxacin, ofloxacin, enoxacin and pefloxacin) in poultry. However, taking into account data obtained in other ACKNOWLEDGMENTS animal species and in man (Gilfillan et al, and Wolfson, 1985; Walker 1984; Hooper This work was supported by the Comision Inter- et al, 1989), they are also likely to have ministerial de Ciencia y Tecnologia, Programa good tissue penetration. A study on the Nacional de Investigacion y Desarrollo Farma- physiological disposition of enrofloxacin ceutico, project FAR 88-0478, Spain. REFERENCES ities in humans. Antimicrob Agents Chemo- ther28, 716-721 Horii S, Yasuoka C, Matsumoto M Baggot JD (1980) Distribution of antimicrobial (1987) High- method in normal and diseased animals. J performance liquid chromatographic agents for the simultaneous Am Vet Med Assoc 176, 1085-1090 determination of oxolinic, nalidixic and piromidic acids in cultured Barry AL (1989) In vitro activities of the quino- fish. J Chromatogr 388, 459-461 lone antimicrobial agents. 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