Interspecies variation in the plasma halflife of oxytetracycline in relation to bodyweight

Research in Veterinary Science 1990,48,180-183

Interspecies variation in the plasma halflife of oxytetracycline in relation to bodyweight J. K. KIRKWOOD, M. A. WIDDOWSON, Department of Veterinary Science, Institute of Zoology, Zoological Society of London, Regent's Park, London NW14RY The relationship between halflife (tv" minutes) of oxytetracycline and bodyweight (W, kg) between species of mammals and birds was examined using data collected from the literature. Linear regression of the logarithm of the halflife of the elimination phase of oxytetracycline following intravenous injection on the logarithm of bodyweight for a variety of species of mammals and birds revealed a significant correlation between .species (r=0'602, n=13, P<0·05). The interspecies relationship was described by the allometric equation; tv, = 160 WO· 20 • This suggests that there is about a 14-fold variation in tv, across the size range of terrestrial homoeotherms, and provides a guide to dosage regime for species in which oxytetracycline kinetics have not been studied. ALTHOUGH there is increasing interest in the veterinary medicine and husbandry of wild animals (Fowler 1986), in general, far less is known about wild animals than the few species that man has domesticated for farming, company or research. There are . 4072 species of mammals (MacDonald 1984), 8805 species of birds (Perrins and Middleton 1985), about 5000 species of reptiles and 3000 species of amphibians (Porter 1972). Thus the terrestrial vertebrates alone represent an enormous and, at best, only patchily chartered part of the phylum with which the veterinary profession concerns itself. It is highly improbable that drug pharmacokinetics will ever be studied in more than a small fraction of the total species in any class of animals. Thus the problem of dosage estimation for individuals of species for which no specific data on drug disposition are available needs consideration. Although it has been suggested that- interspecies comparisons of pharmacokinetic parameters in relation to bodyweight may reveal allometric relationships (see below) that could be used for dose prediction (Kirkwood .1983, 1986, Sedgwick et al 1986), until recently there were few experimental data (Dedrick et a11970, Weiss et aI1977) to support this. Recently, however, several reports of analyses of pharmacokinetic parameters have been published which emphasise the value of this approach for dosage prediction for a variety of drugs (Boxenbaum 1984, Sawada et al 1984, Mordenti

1985). So far these interspecies analyses have been based on data from relatively few species, but reveal statistically significant bodyweight effects. For example, the elimination phase halflives of 12 cephalosporin and monobactam antibiotics have been found to be related, between species, to bodyweight raised to the power, on average, of 0·25 (Mordenti 1985). The form of this relationship is consistent with expectations, since metabolic turnover time (for example, the time taken to utilise a given amount of energy per kg bodyweight) increases with the O' 25 power of weight (Kleiber 1975). As data become available for a wider range of species more sophisticated analyses which test for other effects, for example, phylogeny and diet type, will become possible. Development of the methodology for interspecies comparisons of this type, to enable rational dosage estimation for a wide range of species, is an important step in the widening of the taxonomic boundaries of veterinary medicine. In this paper, variation in the plasma half-life of oxytetracycline following intravenous injection was analysed in relation to bodyweight in a range of mammals and birds, to test the hypothesis that halflife increases with the bodyweight raised to a power close to 0·25. The data were collected from the literature. Materials and methods

Database Values for the halflife (tv, minutes) of oxytetracycline in plasma during the elimination phase following intravenous injection were collected from the literature for a variety of species of mammals and birds. In some of these studies the bodyweight (W, kg) of the animals was not recorded and, in these cases, we have assumed a weight typical of an adult of the species. The database is shown in Table I.

Statistical analysis After logarithmic transformation of the values for halflife and bodyweight for each study shown in

180

Relationship of oxytetracycline haljlife and bodyweight

181

TABLE1: Oxytetracycline halflife Ity,,1 following intravenous injection. and bodyweight (WI. in a variety of species of mammals and birds Species

Order/family

Dog

Carnivora Canidae

Canistamiliaris

Perissodactyla Equidae

Horse

Equus caballus Mean

t% (min)

10·5

360

Baggot et al 1977

630

Pilloud 1973 Teske et al 1973 Brown et al 1981

500" 500" 500" 500

32

Pig

Artiodactyla Suidae

W(kg)

Sus scrota Mean

15·5 30 26

942

482t

Source

685

232

846

225

Mercer et al 1978 Mevius et al 1986 Xia et al 1983·

434

Camelidae

Camel

375

420

EI-Gendi et al 1982

Bovidae

Cow.

452

546t

Yoder et al 1954 Pilloud 1973 Clark et al 1974 Schifferli et al 1982 Nouws et al 1983 Nouws et al 1985

Camelusdromedarius 80S domesticus

500" 160

85

Mean

217

Varma and Paul 1983

Sheep (merino)

100

221

Immelman and Dreyer 1986

360

Anika et al 1986

Goat (dwarf)

38·3

Capra hircus

Galliformes Phasianidae

Rabbit

(

Oryctolagus cun(culus

Red-necked wallaby

Macropusrutogriseus

"

79

10-4

687

Kirkwood et al 1988

152

Teare et al 1985

2

103

Atef et al 1986

10·1

570

Florent and Florent 1986

Pheasant

Gallus domesticus

Turkey

Melleagris gallopavo

McElroy et al 1987

1·5"

Phasmnuscolchicus Chicken

Melleagridae

506

169

avis ovis

Marsupialia Macropodidae

330t 427 618 567

Buffalo

8ubalis bubalus

Lagomorpha Leporidae

500" 603 383

547

If

Assumed bodyweight

t Halflife calculated from tabulated data

Table I, least squares linear regressions of log halflife on log bodyweight were performed on the whole database and on subsets of it selected on taxonomic grounds. This yielded equations of the form: Log tv,

= c+ b.log

W

where c is the intercept and b the slope of the regression line. This equation can be expressed in the allometric form: t y, = a.Wb

where a is the antilog of c. The aim was to determine the values of a and b which define the relationship of tv, and W between species. The problems of the methodology of analyses of this sort, in particular the selection of the taxonomic level at which the analysis should be carried out, for example, strain, species, family, order, etc, have been discussed by Harvey and Mace (1984). For between species comparisons, the mean values for tv, and W

were used for those species for which multiple data were available. For the between family comparison mean tv, and W were calculated from the mean or only values for the species within each family and the between order comparison was made by calculating t~e mean for each order from the family means. Results There is a greater than to-fold range between species in the halflife of plasma oxytetracycline during the elimination phase; from 79 minutes in the rabbit (McElroy et a11987)to 942 minutes in the horse (Teske et al 1973). Some estimates of the duration of halflife in a species vary quite considerably, the most extreme example being from 225 to 846 minutes in the pig. Some factors that may be involved in withinspecies variation are listed later. Visual inspection of the data (Fig I, Table I) suggested that tv, tended to increase with Walthough

182 1000

W T

:5

.§ 500

~co

J:

200

H

0C

-Ph

100

R

Ch 10 20 Weight (kg)

5

100

500

FIG 1: The half/ife of oxytetracycline in plasmaduring the elimination phase after intravenous injection in relation to bodyweight in a variety of speciesof mammalsand birds. The line is the regressionof the logarithm of halflife on the logarithm of bodyweight for all species. 0 Dog; H Horse; P Pig; C Camel; 0 Ox; B Buffalo; S Sheep; G Goat; R Rabbit; W Wallaby; Ph Pheasant; Ch Chicken; T Turkey

there was clearly much variation that was not related to weight. The correlation of log tv, to log Wamong all the measurements listed in Table I was significant at the I per cent level, and the correlation between all the species was significant at the 5 per cent level (Table 2). The allometric equation describing the relationship between species was

tv,

=

160 WO'20

The exponent 0·20 (SEM 0,078) was not significantly different from 0·25. The correlation was also found to be significant among the nine species of eutherian mammals, but not among all mammals (that is, after inclusion of the data for the wallaby). The correlations of mean values of tv, and W among families and among orders were positive but not statistically significant (Table 2). Discussion Among all the measurements and all the species listed in Table I log tv, was found to be significantly correlated with log W, and tv, increased with theO'20 power of bodyweight. This exponent did not differ significantly from O'25. The correlation was also significant among the eutherian mammals and the TABLE 2: Correlation coefficients r and values for the constant a and the exponent b In allometric equations describing the relationship of oxytetracycline halfllfe to bodyweight In a variety of mammals and birds Group

n

a

b

All measurements All species All eutherians All mammals All families All orders

22

162 160 119 171 158 167

0·20 0·20 0·23 0·17 0·23 0·24

NS Not significant

13 9 10 9 6

0·621 0·602 0·713 0·514 0·651 0·670

P<0·01 P<0·05 P
Relationship of oxytetracycline halflife and bodyweight exponent in allometric equations depends upon the sample of species included in the analysis and often also on the taxonomic level at which the analysis is carried out. It is a statistical parameter, not a precisely measurable physical entity. Nevertheless, while determination of what exactly it might be found to be if data for all warm-blooded species were available is not possible, estimates of it such as presented here may enable valid and, in practice, valuable predictions. As far as we are aware there have been no measurements of oxytetracycline kinetics in reptiles. It is perhaps likely that halflives in cold-blooded animals are considerably longer than for homoeotherms of comparable size. Further measurements of halflife and other kinetic parameters in a wider range of species are requiredto elucidate phylogenetic effects. Acknowledgements

The authors are grateful to Professor A. P. F. Flint for his comments on this paper. References ANIKA, s. M., NOUWS, J. F. M., VAN GOGH, H., NIEUWENHUJJS, J., VREE, T. B. & VAN MIERT, A. S. J. P. A. M. (1986) Research in Veterinary Science 41, 386-390 ATEF, M., EL GENDI, A. Y. I., YOUSSEF, S. A. H. & AMER, A. M. M. (1986) Archiv fur Geflugelkunde SO, 144-148 BAGGOT, J. D., POWERS, T. E., POWERS, J. D., KOWALSKI, J. J. & KERR, K. M. (1977) Research in Veterinary Science 24. 77-81 BOXENBAUM, H. (1984) Drug Metabolism Reviews 15.1071-1121 BROWN, M. P., STOVER, S. M., KELLY, R. H., FARVER, T. B. & KNIGHT, H. D. (1981) Journal of Veterinary Pharmacology and Therapeutics 4, 7-10 CALDER, W. A. III. (1984) Size, Function and Life .History. Cambridge, Massachusetts, Harvard University Press CLARK, J. G., ADAMS, C., ADDIS, D. G., DUNBAR, J. R., HINMAN. D. D. & LOFGREEN. G. P. (974) Veterinary Medicine/Small Animal Clinician 69, 1542-1546 DEDRICK, R. L., BISCHOFF, K. B. & ZAHARKO, D. S. (970) Cancer Chemotherapy Report 54, 95-101 EL~GENDI, A. Y. I., EL-SAYED, M. G. A., ATEF, M. & ZAKI HUSSIN, A. (1983) Archives Internationaies de Pharmacodynamie et Therapie261. 186-195 FLORENT, J. M. & FLORE NT, P. M. (1986) Revue de Medecine Veterinaire 137, 651-667 FOWLER, M. E. (ed) (986) Zoo and Wild Animal Medicine. Philadelphia, W. B. Saunders. p 4 . HARVEY, P. H. & MACE, G. M. (1982) Current Problems in Sociobiology. Eds King's College Sociobiology Group. Cambridge University Press. pp 343-361

183

HUBER, W. G. (1982) Veterinary Pharmacology and Therapeutics. Eds N. H. Booth and L. E. McDonald. Ames, Iowa State University Press. pp 740-747 . IMMELMAN, A. & DREYER, G. (1986) Journal of the South African Veterinary Association 57, 103-104 KIRKWOOD, J. K. (1983) Veterinary Record 113, 287-290 KIRKWOOD, J. K. (1986) Proceedings of the Association for Veterinary Clinical Pharmacology and Therapeutics 10. 74-80 KIRKWOOD, J. K., GULLAND, F. M. G., NEEDHAM, J. R. & VOGLER, M. G. (1988) Research in Veterinary Science 44. .335-337 KLEIBER, M. (1975) The Fire of Life. 2nd edn. New York, Robert E. Krieger MACDONALD, D. (ed) (984) The Encyclopaedia of Mammals. London, George AJlen & Unwin. p 2 McELROY, D. E., RAVIS, W. R. & CLARK, C. H. (1987) American Journal of Veterinary Research 48,1261-1262 MERCER, H. D., TESKE, R. H., LONG, P. E. & SHOWALTER, D. H. (1978) Journal of Veterinary Pharmacology and Therapeutics 1,119-128 MEVIUS, D. J., VELLENGA, L., BREUKINK, H. J., NOUWS, J. F. M., VREE, T. B. & DRIESSENS, F. (1986) Veterinary Quarterly 8, 274-284 MORDENTI, J. (1985) Antimicrobial Agents and Chemotherapy 27, 887-891 NOUWS, J. F. M., VAN GINNEKEN, C. A. M. & ZIV, G. (1983) Journal of Veterinary Pharmacology and Therapeutics 6, 59-66 NOUWS, J. F. M., VREE, T. B., TERMOND, E., LOHUIS, J., VAN LITH, P., BINKHORST, G. J. & BREUKINK, H. J. (1985) Veterinary Quarterly 7, 296-314 PERRINS, C. M. & MIDDLETON, A. L. A. (ed) (1985) The Encyctopaedia of Birds. London, George AJlen & Unwin. p 2 PILLOUD, M. (1973) Research in Veterinary Science IS, 224-230 PORTER. K. R. (972) Herpetology. Philadelphia, London, Toronto, W. B. Saunders. pp 113,238 SAWADA, Y., HANANO, M., SUGIYAMA, Y. & IGA, T. (1984) Journal of Pharmacokinetics and Biopharmaceutics 12, 241-261 SCHIFFERLI, D., GALEAZZI, R. L., NICOLET, J. & WANNER, M. (1982) Journal of Veterinary Pharmacology and Therapy 5. 247-257 SEDGWICK, C. J., .tIASKELL, A. & POKRAS, M. A. (1986) Wildlife Rehabilitation 5, 3- I I TEARE, A. J., SCHWARK, W. S., SHIN, S. J. & GRAHAM, D. L. (1985) American Journal of Veterinary Research 46, 2639-2643 TESKE, R. H., ROLLINS, L. D., CONDON, R. J. & CARTER, G. G. (1973) Journal of the American Veterinary Medicine Association 162, 119-120 VARMA, K. J. & PAUL, B. S. (1983) American Journal of Veterinary Research 44, 497-499 WEISS, M. W., SZEIGOLLEIIT, W. & FOSTER, W. (1977) International Journal of Clinical Pharmacology IS, 572-575 XIA, W., GYRD-HANSEN, N. & NIELSEN, P. (1983) Journal of Veterinary Pharmacology and Therapeutics 6, 113-120 YODER, H. W. & PACKER, R. A. (1954) American Journal of Veterinary Research 15,412-416

Received October 27, /988 Accepted July II, /989