Comparison of the Pharmacokinetics of Seven Fluoroquinolones in Mammalian and Bird Species Using Allometric Analysis

Bulgarian Journal of Veterinary Medicine (2009), 12, No 1, 3−24

COMPARISON OF THE PHARMACOKINETICS OF SEVEN FLUOROQUINOLONES IN MAMMALIAN AND BIRD SPECIES USING ALLOMETRIC ANALYSIS

A. M. HARITOVA & L. D. LASHEV Department of Pharmacology, Physiology of Animals and Physiological Chemistry, Faculty of Veterinary Medicine, Trakia University, 6000 Stara Zagora, Bulgaria

Summary

Haritova, A. M. & L. D. Lashev, 2009. Comparison of the pharmacokinetics of seven fluoroquinolones in mammalian and bird species using allometric analysis. Bulg. J. Vet. Med., 12, No 1, 3−24.

Allometric analysis is used to predict the pharmacokinetic behaviour of drugs in animal species where it has not been studied yet. This method was applied to calculate total body clearance, volume of distribution and elimination half-life of seven fluoroquinolone drugs. The results showed that pro- vided information for quinolones’ pharmacokinetics was very close to real data, with the highest accuracy for marbofloxacin. On the contrast, the prediction of pharmacokinetics of enrofloxacin and its active metabolite ciprofloxacin was the most unreliable. Birds should be separately subjected to allometric scaling in order to receive more accurate results. The comparison of data among species showed that in rabbits, pigs, sheep, donkeys and wild animals as gorals, alpakas and oryxes, allometric scaling of fluoroquinolones could not always provide a reasonable accuracy. Therefore, the specificity of metabolism and excretion of a given drug should be taken into account.

Key words: allometric scaling, birds, fluoroquinolones, mammals, pharmacokinetics

INTRODUCTION

Allometric analysis has been used to pre- physiological characteristics as birds and dict the pharmacokinetic behaviour of mammals. Mammalian species could be drugs and to estimate dosage regimens in further divided into carnivores, herbi- animal species that have not been studied vores, or to ruminants and others (Kirk- yet. It also has been used in drug deve- wood & Merriam, 1990; Riond & Riviere, lopment (Mahmood & Balian, 1999) and 1990; Pashov et al., 1997; Riviere et al., in comparison of pharmacokinetics of 1997; Dinev, 2008). This division in different substances between species (Di- groups is based on interspecies differ- nev, 2008). The main assumption of this ences in the physiology and it is aimed to approach is that many physiological pro- predict the specific pharmacokinetic cesses and organ sizes exhibit a power properties of the drugs with a higher ac- law relationship with the body weight of curacy. the species (Mahmood & Balian, 1999). Interspecies pharmacokinetic scaling The allometric scaling is regularly con- has been performed for a large variety of ducted using data for animal species, be- antibacterial agents (Duthu, 1985; Riond longing to taxonomic groups with similar & Riviere, 1990; Pashov et al., 1997; Comparison of the pharmacokinetics of seven fluoroquinolones in mammalian and bird species ...

Riviere et al., 1997; Lashev, 1998). The some differences between fluoroquinolo- most recent data concern fluoroqui- nes. nolones as a class of antimicrobial drugs The objective of this study was to as- which is rapidly developing and widely sess the relationship between elimination used in veterinary medicine (Bregante et half-life, volume of distribution at steady- al., 1999; Cox et al., 2004; Cox, 2007). state, and total body clearance to body Pharmacokinetics of fluoroquinolones weight of seven fluoroquinolone drugs in was extensively studied in a number of different species by the method of al- animal species and after different routes lometric scaling. These data could serve of administration. These drugs have simi- for a better understanding of fluoroqui- lar distribution characteristics, however, nolone pharmacokinetics and could be elimination pathways and rates differ con- further used for prediction of pharma- siderably among species and among qui- cokinetic parameters in rare wild and ex- nolones. Less variations were found out otic species or for first-in-animal dose in rates of absorption. Fluoroquinolones selection. are rapidly absorbed to a high extent and well distributed in different tissues with MATERIALS AND METHODS volume of distribution greater than 1 L/kg in all investigated species (Haritova et al., The allometric analysis of pharmacokine- 2006a). Binding to plasma proteins varies tic parameters of enrofloxacin and its me- among species and for different gyrase tabolite ciprofloxacin, danofloxacin, mar- inhibitors, but in most cases it is low bofloxacin, difloxacin, pefloxacin and its (Zlotos et al., 1998). The major differen- metabolite norfloxacin, was performed ces between animals with regard to elimi- using data from previously published nation are connected with active trans- studies (Tables 1−4). Only data for intra- port, intestinal and hepatic metabolism, venously administered drugs, quantitated and renal excretion. Fluoroquinolones are by microbiological assay or HPLC were metabolized by oxidation, demethylation used. The matrices of interest were serum and deethylation (Lefebvre et al., 1998; or plasma. For analysis of each drug, data Anadón et al., 2002). They are excreted for elimination half-life (t1/2β), volume of with urine by glomerular filtration and distribution at steady-state (V ) and tubular secretion, with the exception of d(ss) total body clearance (ClB) were used. difloxacin which is found mainly in the Data for body weights were collected faeces (Fernandez-Varon et al., 2006b). from the same studies and they referred to These data were used in the allometric healthy adult animals. All values were scaling of pharmacokinetic parameters of calculated on the basis of any single pub- enrofloxacin and its major metabolite lished value of pharmacokinetic parame- ciprofloxacin, marbofloxacin, danofloxa- ters versus body weights of the included cin and difloxacin (Lashev, 1998; Bre- animal species from each study. The gante et al., 1999; Cox et al., 2004; Cox, analysis of data for enrofloxacin was per- 2007). Data about allometric analysis in formed for mammals and birds separately birds were not included in the published and together. Because of the lack of investigations. Fluoroquinolones such as enough pharmacokinetic data for avian pefloxacin and norfloxacin were not sub- species, a separate analysis for other jected to analysis. The findings indicated fluoroquinolones was not performed.

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The simple allometric approach has been A statistically significant relationship based on the following power function: was found between body weight and Vd(ss) as well as between body weight and Cl Y = a.Wb (1) B when all species were analyzed (Table 5). where Y is the value of the respective The highest intercept for Vd(ss) was found pharmacokinetic parameter (t1/2β; Vd(ss) or for danofloxacin and the lowest − for ClB), а is the coefficient equal to antilog marbofloxacin. The values of y-intercept of c in equation 2, W is the body weight were similar for enrofloxacin and cipro- and b is the exponent of allometric equa- floxacin when data about mammals and tion. birds were analyzed together. The same The log transformation of (1) gives: was valid for pefloxacin and norfloxacin. The lowest value of Cl was calculated log Y = logc + b.logW (2) B for marbofloxacin.

where Y is t1/2β, Vd(ss) or ClB, logc is Predicted values of t1/2β, Vd(ss) and ClB the y-intercept and b is the slope. were compared to literature values (Tab- The least squares linear regression les 1−4). The allometric approach had the method was used for estimation of corre- highest predictive power with the lowest lation between pharmacokinetic parame- error with regards to the pharmacokinetic ters of interest and body weight. Statisti- parameters of marbofloxacin, danoflo- cal analysis was done by Statistica 6.1 xacin and norfloxacin. Pigs, rabbits, software (Statistica for Windows, sheep, chickens and turkeys are the ani- StatSoft. Inc., Tulsa, OK, USA). mal species with higher deviation of the predicted vs reported values. RESULTS DISCUSSION Results of the regression analysis con- ducted are listed in Table 5. The values of Simple allometric scaling is an attractive the exponent b for t½β were very low for low-cost and time-efficient alternative to all fluoroquinolones. Its value for Vd(ss) provide reliable predictions of t1/2β, Vd(ss) and ClB was between 0.74 and 1.29 for all and ClB. Despite the risk for deviation of studied drugs, the lowest (0.67) being that the estimated values from the observed of Vd(ss) of danofloxacin. pharmacokinetic parameters in some ca- There was no association between t1/2β ses, interspecies scaling in veterinary me- and body weight in all species and for all dicine could be used to analyze the phar- quinolone drugs of interest. Therefore, macokinetic behaviour of the drugs and to animals were divided into mammals and focus the efforts on providing good ex- birds for allometric scaling of enrofloxa- planations for the observed differences cin, for which enough pharmacokinetic between animal species (Mahmood, data are available. Although the correla- 2007). The experience with allometric tion was improved, a statistically signifi- scaling shows that with higher number of

cant relationship between t1/2β and body the analyzed data, including number of weight was not observed. The highest animal species and number of individual

value of y-intercept for t1/2β was calcu- studies for each species, the method lated for marbofloxacin. would have the best predictive value (Mahmood & Balian, 1999; Mahmood,

12 BJVM, 12, No 1 A. M. Haritova & L. D. Lashev

Table 5. Values of elimination half-life (t½β), volume of distribution at steady state (Vd(ss)) and total body clearance (ClB) for allometric equations

Substance Species n Parameters a b r P 50 t 3.767 −0.006 0.020 >0.05 Mammals, ½β 42 Cl 0.924 0.818 0.918 <0.001 birds B 46 Vd(ss) 3.848 0.794 0.951 <0.001 41 t½β 2.490 0.066 0.241 >0.05 Enrofloxacin Mammals 39 ClB 1.330 0.755 0.911 <0.001 33 Vd(ss) 4.050 0.783 0.941 <0.001 14 t½β 5.600 0.130 0.275 >0.05 Birds 13 ClB 0.245 1.130 0.795 <0.01 13 Vd(ss) 2.660 1.078 0.928 <0.001 22 t 2.794 0.036 0.154 >0.05 Mammals, ½β Ciprofloxacin 30 Cl 0.919 0.875 0.935 <0.001 birds B 26 Vd(ss) 4.167 0.827 0.947 <0.001 17 t 6.300 −0.089 0.045 >0.05 Mammals, ½β Danofloxacin 15 Cl 0.828 0.902 0.933 <0.001 birds B 13 Vd(ss) 10.520 0.665 0.807 <0.001 18 t 6.580 0.003 0.016 >0.05 Mammals, ½β Marbofloxacin 18 Cl 0.168 1.043 0.984 <0.001 birds B 17 Vd(ss) 1.320 0.999 0.995 <0.001 12 t 3.730 0.081 0.348 >0.005 Mammals, ½β Difloxacin 12 Cl 0.734 0.743 0.960 <0.001 birds B 12 Vd(ss) 3.018 0.857 0.978 <0.001 18 t½ 3.010 0.061 0.291 >0.05 Mammals, β Norfloxacin 14 Cl 0.326 1.025 0.907 <0.001 birds B 16 Vd(ss) 2.210 0.970 0.915 <0.001 6 t 3.825 −0.096 0.259 >0.05 Mammals, ½β Рefloxacin 5 Cl 0.357 1.287 0.959 <0.01 birds B 5 Vd(ss) 2.022 0.969 0.962 <0.01

2007). Results in our study confirm this dependent. In general, it is acknowledged observation, therefore, we tried to use as that the inclusion of dogs and rabbits in much data as possible from the published allometry decreases the predictive value literature. Dividing animal species in of the results for humans. At the same groups according to physiological charac- time, inclusion of monkeys and rats im- teristics could improve the predictive proves significantly the results (Tang & power (Mahmood, 2007). Fluoroqui- Mayersohn, 2005). In all cases data for at nolones undergo a more complete conver- least one large species can improve al- sion in mammals than in birds (Lefebvre lometric analysis results (Mahmood, et al., 1998; Dimitrova et al., 2007). 2007). Considering all this experience, Analysis of data for mammals and birds data about enrofloxacin and marbofloxa- separately resulted in more accurate pre- cin in ostriches, nandu and red tailed diction of pharmacokinetic parameters in hawks were excluded from analysis. In our study. these species, extremely short elimination In addition, scaling can be species- half-lives and high total body clearance

BJVM, 12, No 1 13 Comparison of the pharmacokinetics of seven fluoroquinolones in mammalian and bird species ...

values were observed because of quantita- a perfect correlation between weight/ClB tively different activity, multiplicity and and weight/Vd(ss). Therefore, it is not sur- tissue specific expression of drug-meta- prising that b tends to equal zero and is bolizing enzyme systems (Amsallem- far from the theoretical value of 0.25. Our Holtzman & Ben-Zvi, 1997; Bailey et al., results are consistent with the values pub- 1998). Such phenomena are commonly lished by Cox et al. (2004) and Cox observed in interspecies scaling (Pashov (2007) for quinolones (Table 6). In con- et al., 1997; Lashev, 1998; Mahmood, trast, Breagante et al. (1999) found statis- 2007; White et al., 2007). They could be tically significant correlation when results explained with different inter-species me- for enrofloxacin, obtained from the same tabolic and excretion rates, breed-, sex- laboratory and method of analysis, for and age-related differences, or variability five animal species were subjected to in the results from different laboratories. scaling. This observation could explain When the parameters are modeled as the significance of accuracy of data ob- an inverse function of a physiological tained with different methods of analysis. process, the exponent will equal (1−b). In our study the results were not im- Half-life is a secondary parameter, de- proved even when scaling was performed rived of scaling to Vd(ss)/ClB. In that case a after grouping of animals according to slope of zero would be expected if there is their physiological characteristics. Al-

Table 6. Previously published values for elimination half-life, volume of distribution and clearance from allometric equations Substance Species n Parameters a b Reference Mammals, 22 ClB 3.63 0.90 Lashev, 1998 birds 25 Vd(area) 0.55 1.01 39 t 6.8 0.062 Mammals, ½β 39 Cl 0.432 0.939 birds B 39 V 4.11 0.803 Enroflo- d(ss) Cox et al., 2004 32 t½ 4.0 0.062 xacin β Mammals 32 ClB 0.954 0.764 32 Vd(ss) 6.00 0.723 5 t½ 1.926 0.06 β Bregante et al., Mammals 5 Cl 2.87 0.82 B 1999 5 Vd(area) 10.90 0.90 10 Cl 1.04 0.93±0.01 Mammals B Lashev, 1998 10 Vd(area) 2.82 1.07±0.09 Mammals, 38 t½β 5.1 −0.123 birds, fish, 38 ClB 0.35 1.13 reptiles 38 V 2.2 1.07 Ciproflo- d(ss) Cox et al., 2004 32 t½ 2.2 0.091 xacin β Mammals 32 ClB 1.24 0.815 32 Vd(ss) 3.5 0.947 t½ − 0.041 β Mahmood & Mammals Cl − 0.927 B Balian, 1999 Vd(ss) − 0.966 n – number of observations.

14 BJVM, 12, No 1 A. M. Haritova & L. D. Lashev

though a correlation between body weight A very high error in prediction of this

and t½β was not found, the predicted val- pharmacokinetic parameter was observed, ues for the elimination half-life were very that could be partially explained by the close to observed ones. This fact could be physiological condition in camels (water- attributed to a significant correlations deprived). A reasonable explanation for between weight and ClB and weight and the observed error in alpacas could not be Vd(ss). Values of a, representing the rela- given because data about physiological tionship of elimination half-life to body condition were not available. According weight, indicate that the longest t½β for to our data for all investigated drugs, it marbofloxacin and the shortest t½β for could be assumed that scaling of Vd(ss) has enrofloxacin in mammals and for cipro- a low prediction power in rabbits, which floxacin in all animal species could be is difficult to be explained. expected. These results are consistent It is widely accepted that the meta- with the published pharmacokinetic pa- bolic rate is proportional to body mass rameters for the studied quinolones (Ta- raised to the three-quarter power (W0.75). bles 1−4). Moreover, overall renal and hepatic func- The allometric exponent b for most tions are determined by blood flow which pharmacokinetic parameters related to on its turn is dependent on cardiac output physiological processes ranges from 0.67 and therefore, the cardiac output is scaled to 1 (Riviere et al., 1997). Its theoretical to b equal to 0.75 (Mahmood & Balian, value for the volume of distribution is 1999; Atanasov & Dimitrov, 2002; Mah- equal to 1 assuming that total body water mood, 2007). This is not always true, es- directly correlates to body weight and that pecially for drugs that undergo significant Vd is a function of total body water (Mah- conversion. However, our values of b for mood, 2007). Our results for marbofloxa- ClB in mammals differ from 0.75 with cin, difloxacin, pefloxacin and its metabo- exception of results for difloxacin (0.743) lite norfloxacin are close to this theoreti- and enrofloxacin (0.755). One of the ex- cal value. Similar data were reported for planations for these results could be that ciprofloxacin and enrofloxacin by Lashev most fluoroquinolones are excreted not (1998), Bregante et al. (1999) and Cox et only through kidneys and are metabolized al. (2004) (Table 6). In our investigation in the liver. The exponent b is close to 1 and in other studies (Mahmood & Balian, for all other quinolones thus correspond- 1999; Cox, 2007) the exponent b tends to ing to the assumption that the exponent of be close to 0.8 for enrofloxacin, cipro- simple allometric equation should be be- floxacin and danofloxacin. A value close tween 0.7 and 1 in order to predict clear- to 1 was obtained when data for enroflo- ance of the drugs (Mahmood & Balian, xacin in birds were analysed separately by 1999). Similar values were found for en- allometry. These data, the high correlation rofloxacin and ciprofloxacin in several coefficient and the very low P-value al- studies (Lashev, 1998; Bregante et al., low us to conclude that Vd(ss) is propor- 1999; Cox et al., 2004; Cox, 2007). These tional to body weight for all seven studied data and the low P-value allow us to con- fluoroquinolones. Some controversial clude that there was a clear relationship results were obtained for Vd(ss) of enro- between ClB and body weight in our in- floxacin in alpacas and camels and of vestigation. The small number of observa- danofloxacin and norfloxacin in rabbits. tions, included in pefloxacin scaling could explain the highest value of b for ClB

BJVM, 12, No 1 15 Comparison of the pharmacokinetics of seven fluoroquinolones in mammalian and bird species ...

(>1.2). Allometric scaling could have hajwalla, 2002; Mahmood, 2007). Differ- some limitations if the clearance of a ent volume of distribution types can be drug, that is partly metabolized and partly used for accurate prediction of this pa- excreted renally, has to be predicted rameter. In some cases volume of distri- (Mahmood, 2007). Therefore, interpreta- bution in the central compartment (Vc) tion of data requires cautious and sound could be more useful than Vd(ss) because scientific judgement. steady-state is usually not achieved with Altogether, allometric scaling could the first dose (Mahmood, 2007). Elimina- provide information for pharmacokinetics tion half-life could be estimated by simple of quinolones very close to the realistic allometry, from predicted clearance and data. Prediction of pharmacokinetics of volume of distribution and from predicted enrofloxacin and its active metabolite MRT. Grouping animals according to ciprofloxacin is the most unreliable. Ex- their anatomical and physiological char- planation could be found in species- acteristics could solve the problem with related differences in the rate of metabo- high deviation of estimated versus ob- lism of these compounds. Relatively nu- served pharmacokinetic parameters. This merous predicted results differing signifi- is especially true for birds. Before al- cantly from the observed values were lometric scaling and dose calculation, determined for pefloxacin and difloxacin, specificity of metabolism and excretion of mainly due to limited data used for inter- a given drug in a particular species should species scaling. Our data suggest that be taken into consideration. Efforts to pharmacokinetic parameters of marbo- improve allometric scaling should con- floxacin could be predicted with high tinue in order to minimize shortcomings accuracy. Comparing data of this analysis associated with its use. among species, it could be concluded that in pigs, rabbits and donkeys allometric REFERENCES scaling could not always result in reasonable accuracy. Values of t1/2β, Vd(ss) and Abadia, A., J. Aramayona, M. Munoz, J. Pla ClB are also difficult to be predicted in Delfina, M. Saez & M. Bregante, 1994. animal species as gorals, alpacas and ory- Disposition of ciprofloxacin following in- xes. Turkeys and chickens are among travenous administration in dogs. Journal species in which prediction could not be of Veterinary Pharmacology and Thera- always enough accurate. peutics, 17, 384−388. Allometric extrapolation could be af- Abd El-Aty, A. & A. Goudah, 2002. Some fected by the experimental design, spe- pharmacokinetic parameters of pefloxacin cies, analytical errors and variations from in lactating goats. Veterinary Research one laboratory to another (Kirkwood, Communications, 26, 553−561. 2004). There are several methods that can Abd El-Aty, A., A. Goudah, M. Ismail & M. be used for improvement of the prediction Shimoda, 2005. Disposition kinetics of di- of clearance. Some of them are based on floxacin in rabbit after intravenous and intramuscular injection of Dicural. Veterinary correction with maximum life-span poten- Research Communications, 29, 297−304. tial, brain weight, unbound fraction of drugs, incorporation of molecular struc- Abd El-Aziz, M. I., M. A. Aziz, F. A. Soliman & N. A. Afifi, 1997. Pharmacokinetic eva- ture parameters and liver blood flow for luation of enrofloxacin in chickens. British biliary excreted drugs (Mahmood & Sa- Poultry Science, 38, 164−168.

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