Detailed pharmacokinetic (PK) studies in rats were performed (i) to compare the PK of prednisolone (PRN) and loteprednol etabonate (LE, a soft corticosteroid) as well as their common inactive metabolite Δ¹- cortienic acid (Δ¹-CA), (ii) to investigate the excretion of Δ¹-CA after PRN and LE administration, and (iii) to investigate the effect of Δ¹-unsaturation on the excretion of Δ¹-CA versus CA. Following a 10 mg·kg^—1 intravenous bolus dose, the total clearance (CLtot) of PRN (27.0 ± 1.4 mL·min^—1 kg^—1) was significantly lower than that of LE (67.4 ± 11.6 mL·min^—1 kg^—1) or Δ¹ CA (53.8 ± 1.4 L·min^—1 kg^—1) indicating that the metabolism/elimination of PRN in the liver (primarily, conjugation) may be less efficient than that of LE (primarily, hydrolysis) or Δ¹-CA (unchanged). The volume of distribution (Vdss) of PRN (823 ± 78 mL·kg^—1) was significantly lower than that of LE (3078 ± 79 mL·kg^—1) indicating that LE is more distributed to lipophilic tissues. Excretion studies have confirmed that Δ¹-CA is indeed a metabolite of PRN. After intravenous injection of 10 mg·kg^—1, less than 1% of the administered PRN was excreted as Δ¹-CA by 4 h (0.38 ± 0.10% in bile and 0.18 ± 0.04% in urine), significantly less than for LE (17.01 ± 2.09% in bile and 2.53 ± 1.17% in urine) indicating that extent of this metabolic transformation can indeed be affected by molecular design. At doses of 100 mg/kg, the proportion of Δ¹-CA excreted after PRN administration (0.12 ± 0.03% in bile and 0.19 ± 0.03% in urine) was similar to that of CA excreted after hydrocortisone administration (0.11 ± 0.03% in bile and 0.22 ± 0.04% in urine) indicating that the presence of the Δ¹ double bond (Δ¹-unsaturation) does not affect significantly this metabolic conversion.