Page 1159 - Small Animal Clinical Nutrition 5th Edition

Effects of Food on Pharmacokinetics 1207

metabolism of drugs such as the methylxanthines, resulting in predominant pathways used for phase II conjugation reactions.
VetBooks.ir reduced therapeutic efficacy. Several investigations have demonstrated enhanced biotrans-
High mineral intake can complicate drug therapy of specific
formation of volatile anesthetics in obese patients, resulting in
disorders: 1) sodium and hypertension, 2) potassium and hypo-
increased production of the reactive intermediates typically
adrenocorticism, 3) magnesium and feline lower urinary tract responsible for organ toxicity (Bentley et al, 1982). Enhanced
disease and 4) phosphorus and chronic renal failure. hepatic oxidative metabolism of halothane in obese people has
Excessive dietary intake of iodine can lead to a paradoxical resulted in increased serum levels of fluoride and bromide ions;
“iodine toxicosis goiter” through what is referred to as the the former is associated with increased hepatotoxicity. Half-life
“Wolff-Chaikoff effect.” As iodide accumulation by the thyroid elimination of triazolam is prolonged in obese subjects, and
gland increases, so does iodination of tyrosyl residues of thy- clearance following oral administration is reduced, presumably
roglobulin. However, very high iodine levels appear to cause because of decreases in hepatic extraction.
auto-inhibition of iodide organification and thyroglobulin pro- Drug toxicity may be enhanced when the dose administered
teolysis, leading to thyroid hormone deficiency. This phenom- is based on total body mass, but distribution is restricted to lean
enon has been observed in foals born to mares that received body mass, resulting in higher plasma drug concentrations and
excessive iodine supplementation during gestation, as well as in greater exposure to susceptible organs (Corcoran et al, 1989;
other species (Drew et al, 1975; Driscoll et al, 1978). Corcoran and Salazar, 1989). Obese rats appear to be at
Naturally occurring non-nutritive dietary factors that may increased risk for gentamicin and furosemide nephrotoxicity by
influence drug responses include methylxanthines, which may this mechanism (Corcoran et al, 1989; Corcoran and Salazar,
complicate aminophylline therapy, histamine in certain types of 1989). Susceptibility to the toxic affects of these drugs remains
fish, which may interfere with antihistamine treatment and even when the dose is decreased to reflect lean body mass and
tyramine in chicken livers and aged cheeses, which confound to equalize drug exposure. Studies of acetaminophen toxicity in
the action of monoamine oxidase inhibitors. Alcohols and rats have shown that when obese animals are dosed according
antioxidants added to certain nutrient sources as preservatives to fat-free mass, toxicity is increased because of a metabolic
and humectants may have adverse effects as well. Benzoic acid shift toward less sulfation and more glucuronidation (Corcoran
and benzoyl alcohol in commercial fluid and drug preparations, and Wong, 1987). Obesity likewise appears to increase drug
propylene glycol in semi-moist commercial cat food and onion glucuronidation in people. Furthermore, target organs may be
powder in commercial human baby foods may induce oxidative predisposed to drug toxicity by pre-existing obesity-related
erythrocyte damage and Heinz body anemia in cats (Bedford lesions such as hepatic lipidosis.
and Clarke, 1971; Wilkie and Kirby, 1988; Christopher et al, Obesity increases steroid hormone clearance in people
1989; Kaplan, 1995).These substances are no longer common- because of enhanced aromatization and interconversion of
ly used in commercial product manufacturing. androgens to estrogens by adipose tissue (Dunn et al, 1991).
Prednisolone and methylprednisolone succinate clearance in
obese people is also increased, although potential contributions
EFFECTS OF OBESITY ON by increased cardiac output, hepatic blood flow, liver size and
DRUG DISPOSITION hydrolysis by extrahepatic carboxyesterases have not been re-
solved. On the other hand, methylprednisolone clearance
Although complicated by the metabolic effects of overnutrition appears to be decreased, suggesting that obesity may affect spe-
during weight gain or restricted food intake during weight loss, cific oxidative pathways very differently (Dunn et al, 1991).
numerous studies have documented a significant effect of obesi- Although similar studies have not been conducted in com-
ty on drug metabolism in people and other animals (Rei- panion animals, certain generalizations can be made. Obesity
denberg, 1977). Changes in the apparent volume of distribution will result in changes in the effective dose administered for
have been observed because of alterations in the quantity of drugs given according to total body weight, whether it is
body fat. Obesity increases the volume distribution of lipophilic increased because of poor lipid solubility or decreased because
drugs such as alprazolam,carbamazepine,diazepam,methotrex- of lipophilicity. Drug dose or dosing interval may need to be
ate, oxazepam, sufentanil and vancomycin. Increased volume adjusted to maintain therapeutic effect and protect against tox-
distribution for lipophilic drugs (e.g., thiobarbiturates) necessi- icity. Alterations in body composition concurrent with drug
tates administration of a higher dose to achieve the desired clin- administration may have significant effects on clinical efficacy
ical response. Sequestration in body fat may prolong the drug’s and margin of safety, and must be considered whenever a
action. Obesity decreases the volume distribution of polar com- patient’s body weight changes markedly (Caraco et al, 1992).
pounds including acetaminophen, ciprofloxacin, furosemide,
gentamicin, isoniazid, sulfisoxazole and tolbutamide (Du- SUMMARY
charme et al, 1994; Dunn et al, 1991; Caraco et al, 1992;
Abernethy et al, 1984; Shum and Jusko, 1984; Yuk et al, 1988; Quantitatively and qualitatively, ingested nutrients have major
Fleming et al, 1991; Schwartz et al, 1991; Allard et al, 1993). effects on the biologic activity of pharmacologic agents. This is
Drug clearance may be affected following changes in hepat- true not just for orally administered drugs in the GI tract, but
ic microsomal enzyme induction, as well as alterations in the also for drugs administered parenterally. Ingested nutrients may