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

被引:23
作者
STELLA, VJ [1 ]
LEE, HK [1 ]
THOMPSON, DO [1 ]
机构
[1] UNIV KANSAS, CTR DRUG DELIVERY RES, LAWRENCE, KS 66045 USA
关键词
METHYLPREDNISOLONE; PHARMACOKINETICS; PRODRUG; PHOSPHATE ESTER; HEMISUCCINATE ESTER; CYCLODEXTRIN; ANIONIC; SBE4-BETA-CD; SULFOBUTYL ETHER; RAT;
D O I
10.1016/0378-5173(94)00404-S
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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/ethanol/water) mixture, a 0.075 M SBE4-beta-CD solution (a sulfobutyl ether derivative variably substituted on the 2-, 3- and the 6-positions of beta-cyclodextrin) and as its two water-soluble prodrugs, the 21-phosphate ester, disodium salt and the 21-hemisuccinate ester, monosodium salt. The aim of the work was to assess what effect the SBE4-beta-CD would have on methylprednisolone pharmacokinetics while the comparison to the prodrugs would provide some insight into a formulation versus a chemical approach to the parenteral delivery of a sparingly water-soluble drug. The plasma concentration-time curves and the pharmacokinetic parameters of methylprednisolone from the SBE4-beta-CD solution and co-solvent mixture were not significantly different. For example, the AUC +/- S.E. values from zero to infinity of methylprednisolone from the co-solvent and the SBE4-beta-CD solutions were 326.7 +/- 20.6 and 317.4 +/- 15.4 mu g min ml(-1), respectively. The AUC values of methylprednisolone from its 21-phosphate and 21-hemisuccinate esters were 59.2 +/- 4.4 and 33.17 +/- 5.3% of that from the co-solvent, respectively. These results confirm that i.v. administered drugs such as methylprednisolone, appear to be rapidly and quantitatively released from SBE4-beta-CD inclusion complexes. Modified cyclodextrins such as SBE4-beta-CD may provide an alternative to the use of co-colvents, and possibly even prodrugs, for the parenteral delivery of sparingly water-soluble drugs such as methylprednisolone.
引用
收藏
页码:189 / 195
页数:7
相关论文
共 21 条
[1]   COMPLEXATION OF STEROID-HORMONES WITH CYCLODEXTRIN DERIVATIVES - SUBSTITUENT EFFECTS OF THE GUEST MOLECULE ON SOLUBILITY AND STABILITY IN AQUEOUS-SOLUTION [J].
ALBERS, E ;
MULLER, BW .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1992, 81 (08) :756-761
[2]   EFFECTS OF BETA-CYCLODEXTRINS AND GAMMA-CYCLODEXTRINS ON THE PHARMACOKINETIC BEHAVIOR OF PREDNISOLONE AFTER INTRAVENOUS AND INTRAMUSCULAR ADMINISTRATIONS TO RABBITS [J].
ARIMORI, K ;
UEKAMA, K .
JOURNAL OF PHARMACOBIO-DYNAMICS, 1987, 10 (08) :390-395
[3]  
BREWSTER ME, 1989, J PARENT SCI TECHN, V43, P231
[4]  
EBLING WF, 1985, DRUG METAB DISPOS, V13, P296
[5]   BIOAVAILABILITY AND NONLINEAR DISPOSITION OF METHYLPREDNISOLONE AND METHYLPREDNISONE IN THE RAT [J].
HAUGHEY, DB ;
JUSKO, WJ .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1992, 81 (02) :117-121
[6]  
IRIE T, 1982, J PHARMACOBIO-DYNAM, V5, P741
[7]   DISPOSITION OF METHYLPREDNISOLONE AND ITS SODIUM SUCCINATE PRODRUG INVIVO AND IN PERFUSED LIVER OF RATS - NONLINEAR AND SEQUENTIAL 1ST-PASS ELIMINATION [J].
KONG, AN ;
JUSKO, WJ .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1991, 80 (05) :409-415
[8]   BETA-CYCLODEXTRIN STEROID COMPLEXATION - EFFECT OF STEROID STRUCTURE ON ASSOCIATION EQUILIBRIA [J].
LIU, FY ;
KILDSIG, DO ;
MITRA, AK .
PHARMACEUTICAL RESEARCH, 1990, 7 (08) :869-873
[9]   COMPARATIVE PHARMACOKINETICS OF METHYLPREDNISOLONE PHOSPHATE AND HEMISUCCINATE IN HIGH-DOSES [J].
MOLLMANN, H ;
ROHDEWALD, P ;
BARTH, J ;
MOLLMANN, C ;
VERHO, M ;
DERENDORF, H .
PHARMACEUTICAL RESEARCH, 1988, 5 (08) :509-513
[10]   SYSTEMIC BIOAVAILABILITY AND PHARMACOKINETICS OF METHYLPREDNISOLONE IN PATIENTS WITH RHEUMATOID-ARTHRITIS FOLLOWING HIGH-DOSE PULSE ADMINISTRATION [J].
NARANG, PK ;
WILDER, R ;
CHATTERJI, DC ;
YEAGER, RL ;
GALLELLI, JF .
BIOPHARMACEUTICS & DRUG DISPOSITION, 1983, 4 (03) :233-248