Failure of Drug Metabolism and Excretion
Jennifer L. Davis
Hepatic disease can affect drug metabolism in several ways. Ascites, if present, can alter drug distribution, and drug dosages should be adjusted based on lean body weight, estimating the amount of fluid present.1 Also, since the liver is the primary organ involved in the metabolism of exogenously administered substances and represents an important method for excretion of drugs via the bile, liver disease can affect drug metabolism and clearance.
Factors influencing hepatic drug metabolism and clearance include hepatic blood flow, hepatic metabolism, and protein binding. Drugs are often classified as having high hepatic extraction ratios (flow-limited drugs) or low hepatic extraction ratios (capacity-limited drugs). Flow-limited drugs are quickly and efficiently extracted by the liver, and their rate of elimination is limited only by hepatic blood flow. Chronic liver disease with decreased parenchymal blood flow or hepatic shunts can decrease blood flow in the liver and greatly compromise clearance of flow-limited drugs like morphine, verapamil, and lidocaine.1 These drugs undergo a high first-pass metabolism following oral administration and, as such, are usually given at high oral doses. The dosage of these drugs may need to be decreased by up to 50% in patients with liver disease because bioavailability will be greatly increased and elimination decreased, possibly resulting in toxic levels of the drug.1,2 The opposite may be true for drugs that require hepatic activation (prodrugs), and thus subtherapeutic levels may be present.3
Capacity-limited drugs are slowly extracted by the liver, and their elimination is independent of blood flow but highly dependent on hepatocellular uptake and metabolism. The effect of liver disease on drug metabolism in these cases is more variable, and drug clearance can be increased, as with atenolol, or decreased, as with diazepam and chloramphenicol.1,2 The majority of phase I (oxidation-reduction) reactions and phase II (glucuronidation) reactions take place in the hepatocytes, and diseases that result in hepatocellular destruction can reduce the ability of the liver to metabolize drugs.
The purpose of these reactions is to make compounds more water-soluble and prepare them for excretion via the kidney. Clearance of drugs eliminated by phase I reactions can be significantly decreased with hepatic disease, whereas phase II reactions are often not affected unless severe disease is present or certain types of glucuronidation are needed.4,5 For example, ester glucuronidation will be decreased in patients with cirrhosis of the liver, and drugs cleared via this pathway will have lower clearance rates compared to drugs metabolized by ether glucuronidation.4Humans with intrahepatic cholestasis showed a decreased activity of phase I cytochrome P450 enzymes and impaired microsomal drug metabolism in vitro, and this was well correlated with serum concentrations of total bilirubin and bile acids.6 Making direct correlations between human drug metabolism and veterinary species is difficult, as there is a large interspecies variation in the types and activity of hepatic metabolizing enzyme among humans, horses, and cattle.7,8 In addition, polymorphisms within some metabolizing enzymes (i.e., CYP2D50) have been demonstrated in horses, resulting in poor, extensive, and ultra-rapid metabolism of related drugs.9 Further classification of the equine and bovine P450 enzymes and their roles in drug metabolism is needed.
Cholestatic diseases have been shown to decrease biliary excretion of a number of drugs in both animal models of disease and human patients with naturally occurring biliary obstruction. Increased plasma levels, prolonged mean residence times, increased area under the concentration-time curve, and decreased total body clearance have all been demonstrated.10-12 In horses administered enrofloxacin intravenously, those animals with GGT activity greater than 200 U/L had a lower clearance and higher area under the curve than horses with GGT activity less than 200 U/L.13 Renal clearance of some drugs may be increased as a compensatory response for the impaired biliary excretion, as is the case with cefpiramide in cholestatic human patients.14 This decreased biliary clearance can be used to an advantage in certain instances when treating biliary tract infections in order to attain higher concentrations of the drug in the bile ducts, as long as the drug has a large therapeutic index.14
A deficiency in hepatic drug metabolism capacity may impair drug metabolism and elimination in young animals.
This has been demonstrated in foals administered chloramphenicol, which is extensively metabolized in the liver via glucuronic acid conjugation and primarily excreted through the biliary system into the feces. Clearance was decreased and half-life prolonged in animals less than 1 week of age.15 Nonsteroidal antiinflammatory drugs (NSAIDs) also show impaired metabolism in neonatal foals. Phenylbutazone, ketoprofen, and flunixin meglumine all have prolonged terminal half-lives over the first few weeks of life.16-18 Neonatal foals also have a low capacity to metabolize enrofloxacin to ciprofloxacin. Ciprofloxacin was not detectable in foals, whereas in adult horses ciprofloxacin concentrations are about 17% of the enrofloxacin concentrations.19 Drug metabolism also differs in neonatal calves and sheep, which may result in prolonged withdrawal times necessary for veal calves and lambs. Studies have shown that hepatic metabolic enzymes are similar to adult levels in sheep and calves by 7 days of age. , At this point, no quantitative research that specifically examines the development of metabolic pathways in the neonatal foal has been performed. It is likely these pathways are decreased in the early stages but rapidly develop and are within a range similar to adult horses within the first 1 to 4 weeks of life, as is seen in other veterinary species.