Horses clearance

On the other hand, acidic drugs tend to ionize under conditions of alkaline pH and so are unable to permeate the renal tubular epithelium and are preferentially excreted. Tire converse applies to conditions of acidic urinary pH. This has been demonstrated experimentally for many drugs weak bases are excreted more rapidly in acidic urine, whereas weak acids are excreted more rapidly in alkaline urine. In the horse, phenylbutazone, which is a weak organic acid with a pKa of 4.6, has a more delayed clearance time under conditions of aciduria than under conditions of alkaline urine. 

The 2-arylpropionic acid ( profen ) non-steroidal anti-inflammatory drugs, each of which contains a single chiral center, are formulated as racemic (50 50) mixtures of the S(+)- and R(-)-enantiomers, with the exception of naproxen, which is formulated as the S(- -)-enantiomer. Based on inhibition of cyclooxygenase activity, the S(- -)-enantiomer is the eutomer (more potent enantiomer). These drugs differ markedly in both pharmacodynamic activity and pharmacokinetic behavior and, in addition, enantiomer pharmacokinetics of each drug varies among animal species. After intravenous administration of racemic keto-profen to horses, sheep, and 20-week-old calves and measurement of individual enantiomers in plasma, significant differences between the enantiomers were found in systemic clearance in horses and in both systemic clearance and volume of distribution in sheep... 

Trimethoprim is metabolized in the liver to oxide and hydroxyl metabolites. It is eliminated by glomerular filtration and active tubular secretion in the kidneys. In horses, a large percentage of trimethoprim is metabolized before excretion in urine (46%) and feces (52%). The clearance of trimethoprim is affected by urine pH, plasma concentrations and the degree of hydration. In horses, the half-life of trimethoprim is 2-3 h and for pyrimethamine it is 12 h. 

The macrolides distribute well and tissue concentrations may be higher than serum concentrations. Erythromycin concentrates and is active in leukocytes because of its high lipid solubility and ion trapping. The of erythromycin is 3.7-7.21/kg in adult horses and foals. The protein binding is low. The hepatic clearance of the macrolides may be slower in animals of up to 1 month of age than in adult animals. 

Cederberg C, Andersson T, Skanberg 11989 Omeprazole pharmacokinetics and metabolism in man. Scandinavian Journal of Gastroenterology Supplement 166 33-42 Clark C K, Merritt A M, Burrow J A et al 1996 Effect of an aluminum-magnesium hydroxide antacid and BSS on gastric pH in horses. Journal of the American Veterinary Medical Association 208 1687-1691 Clarke L L, Argenzio R A, Roberts M C 1990 Effect of meal feeding on plasma volume and urinary electrolyte clearance in ponies. American Journal of Veterinary Research 51 571-576... 

After i.v. administration to horses, the clearance of methocarbamol from plasma is dose dependent lower clearance was calculated after higher doses were administered (Plumb 1995). The elimination half-life in horses (30 mg/kg) was 60-90 min. After oral administration, at dose rates of 50 and 100 mg/kg, peak plasma concentrations occurred within 15-45 min and the bioavailability was 51-124% (Muir et al 1984). Methocarbamol is metabolized to a dealkylated and a hydroxylated product. These two metabolites are found primarily as glucuronide and sulfate conjugates. Methocarbamol crosses both the placenta and the blood-brain barrier. 

There are no pharmakinetic data on the ACE inhibitors in the horse. In humans, enalapril is 60% absorbed following oral administration and is de-esterified in the liver to its active form enalapri-lat it undergoes renal clearance. Both the liver and kidneys eliminate the active forms of benazepril (benazeprilat) and ramipril (ramiprilat). 

In the presence of inflammation, the pharmacokinetics of NSAIDs may be altered. For example, in one study comparing with normal horses, the clearance and of phenylbutazone were increased in horses with experimentally induced inflammatory loci (Mills et al 1996). Horses with experimentally induced inflammation also cleared ketoprofen faster than normal horses (Owens et al 1995a). 

The physiological mechanisms by which phenylbutazone is cleared from the body in the horse have not been well described. In one study, renal clearance accounted for only 25% of the total drug administered (Lees et al 1985). It has been hypothesized that biliary excretion with subsequent fecal elimination represents the primary clearance mechanism of phenylbutazone in the horse (Lees et al 1985). Renal excretion, of an as yet unidentified phenylbutazone metabolite, may also account for a proportion of total body clearance of the compound. 

Excretion of phenylbutazone into the urine can vary depending on the pH of the urine. Because phenylbutazone is a weak acid, in alkaline urine more of the compoimd will be in the ionized form and the excretion rate will be increased, a process referred to as ion trapping (Moss Haywood 1973). In contrast, more of the compound will tend to be in the unionized form in acidic urine, thereby favoring the re-absorption of the compound and prolonging the clearance. It is important to note that most horses not in training produce alkaline urine, but after intense exercise, such as a race, performance horses will produce acidic urine (Wood et al 1990). 

Carprofen, a propionic acid derivative, is an effective analgesic and weak anti-inflammatory agent. Carprofen contains a chiral center at the C2 of the propionic moiety and, therefore, exists in two stereoisomeric forms, the S(-l-)- and P(-)-enan-tiomers. The approved product for the horse is a racemic mixture of the two antipodes. In the horse the S(+)-form has more rapid clearance, as a result of selective glucuronidation and subsequent biliary excretion of that enantiomer (Soraci et al 1995). Unlike many NSAIDs in the horse, the half-life of carprofen is long, with estimates ranging from 14 to 31 h (Lees et al 1994, McKellar et al 1991). Despite the slow clearance, there was no evidence of accumulation of carprofen in plasma when... 

The influence of the active metabolites becomes more significant with repeated administration of the parent drug, as might occur for the control of seizures (see Ch. 9), or chronic oral administration for continued sedation of a neonatal foal. Foals less than 21 days of age have a lower total body clearance of diazepam than older foals and adult horses and, therefore, a greater tendency to develop effects caused by drug accumulation (Norman et al 1997). 

Ketamine undergoes hepatic biotransformation in the horse. The primary metabolites are norketamine and dehydronorketamine (Delatour et al 1991, Sams Pizzo 1987, Seay et al 1993). Up to 40% of ketamine can be excreted unchanged in the urine. Upon recovery from ketamine anesthesia, 40% of the ketamine dose still remains in the horse at levels insufficient to produce anesthesia (Kaka et al 1979). In the horse, the elimination half-life of ketamine is reported to be 42-65 min with a total body clearance of 23-26 ml/kg/min (Kaka et al 1979, Waterman et al 1987). 

In that study, propofol had an elimination half-life of 69 min in the horse, with a total body clearance of 33ml/kg/min. The principal site of elimination of propofol is the liver however, the clearance of propofol exceeds hepatic blood flow, suggesting an extrahepatic site of metabolism (Kuipers et al 1999). In dogs, propofol undergoes biotransformation to 4-hydroxypropofol by cytochrome P450 enzymes (Court et al 1999). 

Willoughby R A, Ecker G L, McKee S L et al 1991 Use of scintigraphy for the determination of mucociliary clearance rates in normal, sedated, diseased and exercised horses. Canadian Journal of Veterinary Research 55 315-320... 

Enrofloxacin is mainly eliminated by hepatic metabolism, and systemic clearance of the drug varies between species. In sheep, horses, dogs and pigs the average clearance of enrofloxacin is in the range 5.75-8.56 mL/min kg, while enrofloxacin clearance (mL/min kg) differs more widely between other species rabbits (17.9), llamas (12.0), chickens (3.3), turkeys (8.9), houbara bustard (5.7) and fingerling rainbow trout (Oncorhynchus mykiss) at 15°C (1.25). Systemic clearance of enrofloxacin represents mainly hepatic clearance composed of a variety of metabolic pathways, which include N-deethylation to ciprofloxacin. 

The systemic clearance of ciprofloxacin in sheep, horses, dogs and pigs is in... 

Table 3.8 Comparison of the systemic clearance (mL/min kg) of bilirubin, marker substances and some drugs eliminated by the liver in horses fed and fasted for 72 h. Results are expressed as mean + SD.

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