THE EFFECT OF SBE4-BETA-CD ON IV METHYLPREDNISOLONE PHARMACOKINETICS IN RATS - COMPARISON TO A COSOLVENT SOLUTION AND 2 WATER-SOLUBLE PRODRUGS

The i.v. pharmacokinetics of methylprednisolone (20 mg/kg) in six rats were studied after administration in a co-solvent (60:12:28 PEG 400/e thanol/water) mixture, a 0.075 M SBE4-beta-CD solution (a sulfobutyl e ther derivative variably substituted on the 2-, 3- and the 6-positions of beta-cyclodextrin) and as its two water-soluble prodrugs, the 21-p hosphate ester, disodium salt and the 21-hemisuccinate ester, monosodi um salt. The aim of the work was to assess what effect the SBE4-beta-C D would have on methylprednisolone pharmacokinetics while the comparis on to the prodrugs would provide some insight into a formulation versu s a chemical approach to the parenteral delivery of a sparingly water- soluble drug. The plasma concentration-time curves and the pharmacokin etic parameters of methylprednisolone from the SBE4-beta-CD solution a nd co-solvent mixture were not significantly different. For example, t he AUC +/- S.E. values from zero to infinity of methylprednisolone fro m the co-solvent and the SBE4-beta-CD solutions were 326.7 +/- 20.6 an d 317.4 +/- 15.4 mu g min ml(-1), respectively. The AUC values of meth ylprednisolone from its 21-phosphate and 21-hemisuccinate esters were 59.2 +/- 4.4 and 33.17 +/- 5.3% of that from the co-solvent, respectiv ely. These results confirm that i.v. administered drugs such as methyl prednisolone, appear to be rapidly and quantitatively released from SB E4-beta-CD inclusion complexes. Modified cyclodextrins such as SBE4-be ta-CD may provide an alternative to the use of co-colvents, and possib ly even prodrugs, for the parenteral delivery of sparingly water-solub le drugs such as methylprednisolone.