Why can't cats efficiently convert prednisone to prednisolone and how does this affect clinical dosing?

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Cats have low bioavailability of oral prednisone compared to prednisolone, making prednisolone the preferred oral glucocorticoid in this species. Although interconversion between the two drugs occurs in cats, a single 2 mg/kg oral dose of prednisolone produces approximately 4-fold higher plasma prednisolone area under the curve compared to the same dose of prednisone. 1 Body condition further amplifies glucocorticoid exposure in cats. Over-conditioned cats achieve approximately 2-fold higher plasma drug concentrations compared to normal-conditioned cats after the same oral dose, which likely explains their perceived increased risk for glucocorticoid-associated side effects including hepatic lipidosis and diabetes mellitus. 1 Dosing based on lean body mass or ideal body weight is recommended in over-conditioned cats. 1 The clinical consequence of poor prednisone bioavailability is that cats require prednisolone specifically, and at higher doses than dogs for equivalent glucocorticoid effect. For long-term glucocorticoid replacement in feline primary hypoadrenocorticism, the final maintenance prednisolone dose is approximately 0.3 mg/kg/day — substantially higher than the commonly recommended 0.05 to 0.1 mg/kg/day used in dogs. 2 The most likely explanation is reduced density of glucocorticoid receptors in feline tissue and lower binding affinity of glucocorticoids at those receptors. 2 Despite higher required doses, cats are more resistant than dogs to the metabolic side effects of glucocorticoids. At anti-inflammatory doses, prednisolone-treated cats show increases in monocyte count and serum albumin, cholesterol, and triglyceride concentrations, but these values remain within reference ranges (with the exception of triglycerides). 3 Dogs receiving comparable anti-inflammatory prednisone doses routinely exceed reference ranges and additionally develop increased alkaline phosphatase and alanine transferase activities, decreased chloride concentration, and decreased u