Lecture 7 2/8/24 Flashcards
How does volume increase as body weight increases?
proportionally, in a 1-to-1 ratio
How does surface area increase as body weight increases?
less than proportionally, in approximately a 2/3-to-1 ratio
How do surface area and body weight relate to basal metabolic rate?
-small species have a larger surface area:body weight ratio
-larger surface area:body weight ratio leads to increased rates of heat loss and higher basal metabolic rate
-larger animals have more structural body material and less metabolically active mass
What is important about adjusting for physiology in pharmacokinetic time?
often, the half-life rates of drugs are “the same” across species when adjusted based on heart rate and other factors
How is clearance related to weight?
-allometrically
-weight^0.67 or weight^0.75
How is Vd related to weight?
-isometrically
-weight^1
What are exceptions to pharmacokinetic considerations?
-drugs eliminated by “non flow-dependent” mechanisms
-drugs eliminated by species-specific metabolism
-genetic polymorphisms
What are the dose extrapolation exceptions?
-drugs eliminated by liver via low-extraction mechanisms
-drugs with saturable absorption and/or elimination at commonly used doses
-saturability that is species-specific and not related to surface area
-drugs eliminated by species-specific liver metabolism
-drugs with significant differences in protein binding across species
-genetic polymorphisms affecting breed of interest in extrapolation
-species-specific differences in entero-hepatic circulation
-drugs with significant tubular reabsorption sensitive to urine pH
-drugs that induce alterations in physiology
Why is acetaminophen toxic to cats?
-drug is metabolized by P-glycoproteins into a highly reactive metabolite
-highly reactive metabolite is often metabolized by glucuronide and sulfate conjugation, which cats are deficient in
-cats scavenge the highly reactive metabolite via glutathione, which eventually is depleted, causing toxicity
What issue do collies have with drug breakdown?
-collies have a mutated MDR1/p-glycoprotein
-p-glycoproteins act as pumps that clear drugs and toxins
Why is the renal-portal system in reptiles of importance?
it leads to more intense hepatic first pass
When is metabolic body size important, besides species extrapolation?
drugs with a very narrow therapeutic window, such as chemotherapy
How can clearance be used across species for dose-adjustment?
dose species 2 = dose of species 1 (CL of species 2/CL species 1)
When can clearance be used across species for dose-adjustment?
when protein binding is similar between the species being compared
