Br. vet..[. (1994). 150, 499

E D I T O R I A L

S P O R T , S C I E N C E A N D M E D I C A T I O N

Physical exercise is generally recommended as a good thing both for normal healthy people and also in many cases for patients with a variety of diseases. If these patients are taking any medication, however, care should be taken to remember that exercise will produce a number of physiological effects, some of which could modify, perhaps quite profoundly, drug disposition. In the case of insulin, for example, there is evidence that increased absorption during exercise may contribute to exercise-induced hypoglycaemia (van Baak, 1990).

At present these findings would appear to have few practical concerns for clini- cal veterinary medicine, but they serve to illustrate the need to consider what may influence the relationship between drug concentrations and drug effects. At pre- sent, in animals, the potential for interaction between physiological states such as exercise and drug absorption and disposition is virtually unexplored. There can also be forensic implications; for example, differences in urinary pH may mark- edly affect the excretion rates of certain drugs. CQmpetition horses often have acidic urine after strenuous exercise and, as such, there will be reduced excretion of weakly acidic drugs. Two such drugs are phenylbutazone and furosemide which are still permitted under the rules of racing in certain jurisdictions in the United States.

Usually, of course, the question is not to study the effects exercise may have on drug excretion, distribution and metabolism, but how drugs may influence exer- cise. Contrary to the popular view, however, few definitive studies have been per- formed that unequivocally demonstrate the ability of a drug to alter the perform- ance of a horse (Kamerling, 1993). Perhaps furosemide is a classic example of a substance with clear pharmacological effects and which is often assumed to influ- ence performance. In reality, it has limited (if any) proven potential to affect ath- letic ability, although it may, under some circumstances, restore performance that has declined due to a furosemide-treatable problem, such as exercise-induced pul- monary haemorrhage (Tobin & Woods, 1989). The advent of the high-speed treadmill has allowed more critical evaluation of drug effects on performance- related variables. When Hinchliff et al. (1993) gave furosemide to horses running on a treadmill, they found that the drug did alter the energetic response to run- ning; the mechanism is unclear but it seems that furosemide-induced diuresis leading to weight reduction may, at least in part, have improved the effic/ency of running-- i f not actual performance.

In this issue of the journal, Professor Steven Kamerling and Dr Jane Owens examine models for assessing the relationship between drug concentration and

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500 BRITISH VETERINARY JOURNAL, 150, 6

drug effect ill pe r fo rmance horses (IZalmerling & Owens, 1994). They discuss how exercise may affect drug distribution as increased blood flow to exercising muscles increases drug delivery and washout. To p roduce all effect, a drug must obviously be present in adequate amounts at the site of action and, a l though a close relationship often exists between drug effect and plasma concentra t ion, some drugs will exer t an effect before they are detectable ill plasma and others after they have disappeared from the vascular compar tment . Because not all drug actions correlate with plasma kinetics, pharmacodynamic models of drug action have been developed which help to assess more accurately drug effects over time.

During the 1980s, work on non-steroidal anti- inflammatory drugs (NSAIDs) in ponies demons t ra ted that knowledge of plasma concentra t ions alone was insuf- ficient as a means of predict ing the time course of a part icular drug's action in the body (for review, see Lees et al., 1987). For example, using an acute non- immune model of inflammation, the distribution of phenylbutazone and its principal active metabolite, oxyphenbutazone was measured in a variety of body fluids; phe- nylbntazone el imination half-lives f rom plasma, and inf lammatory exudate were 4.8 and 24 h, respectively (Lees et al., 1986). The informat ion from these studies and work with o ther NSAIDs provided clinicians with more relevant data than con- ventional plasma clearance studies for predict ing the time-course of action of the drugs. Because concentra t ions ill acute inflammatory exudate were shown to last longer than those in plasma, all explanat ion was provided for the apparen t anom- aly whereby a drug with a short plasma el imination half-life has a p ro longed thera- peutic effect.

Some regulatory authorit ies ill horse sports are current ly consider ing the estab- l ishment of additional drug thresholds based upon plasma or ur ine concen- trations. They should perhaps proceed with caution. As Kamerling and Owens point out, drug effects can occur despite low or even undetec table plasma concen- trations; moreover , urine concentra t ions are often dissociated ill time from those in plasma. The use of appropr ia te pharmacodynamic models and studies of drug metabolism in the exercising horse will compl iment plasma pharmacokinet ics in accurate de terminat ion of drug efficacy and in the establishment of drug thresholds.

A.J. HiGh,ms Editor

REFERENCES

VAN B.~ , M. A. (1990). Influence of exercise on the pharmacokinetics of drugs. Clinical Pharvnacokinetics 19, 32--43.

HINCHLIFF, K. W., McKI-zEVER, K. H., MUIR, W. W. & SAMS, R. (1993). Effect of furosemide and weight carriage on energetic responses of horses to incremental exertion. American Journal of Veterinary Research 54, 1500-4.

KA,XlERLI,~¢;, (1993). Assessment of drug effects on performance. Veterinary Clinics of North America (Equine Practice) 9, 493-510.

K-~.XlERI.IN(;, S. G. 8c OWENS, J. G. (1994). Models for assessing the relationship between drug concentration and drug effect in performance horses. British Veterinary Journal 150, 507-25.

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LEES, P., TAYLOR, J. B. O., HIGGINS, A. J. & SHARMA, S. C. (1986). Phenylbutazone and oxyphenbutazone distribution into tissue fluids in the horse.Journal of VetelinaTy Pharma- colo~ and Therapeutics 9, 204--12.

LrEs, P., HIG(;INS, A.J., SEDGWICK, A. O. & MA'~, S. A. (1987). Applications of equine models of acute inflammations. Veterinary Record 120, 522-9.

TomN, T. & WooDs, W. E. (1989). Detection times and clearance times for drugs in racing horses. Proceedings of the 1 l th Bain-Fallon Memorial Lectures, Australian Equine Veterinary Association, 105-13.