title: Partitioning of anti-inflammatory steroid drugs into phosphatidylcholine and phosphatidylcholine-cholesterol small unilamellar vesicles as studied by second-derivative spectrophotometry.
abstract: The partition coefficients (Kps) of six anti-inflammatory steroid drugs, dexamethasone (DMS), betamethasone (BMS), triamcinolone acetonide (TCLA), fluocinolone acetonide (FCLA), betamethasone 17,21-dipropionate (BMSDP), and clobetasole propionate (CBSP), for phosphatidylcholine (PC), and PC-cholesterol small unilamellar vesicles (SUVs) were determined by a second-derivative spectrophotometric method. The Kp values were obtained with a relative standard deviation of below 10% and the following order was observed: BMS< or =DMS<TCLA<FCLA<<BMSDP<CBSP. BMSDP which has a structure that the two hydroxyl groups of BMS are esterified with propionic acid showed a largely enhanced Kp value of 10.5 times that of BMS. Further, replacement of a propionate group in BMSDP with a chlorine atom resulted in the highest Kp value (CBSP) within the drugs examined, i.e., the Kp value of CBSP was 1.2 times that of BMSDP. The presence of 30 mol% cholesterol in the SUV bilayers reduced these Kp values to approximately 35-50% of those values for the PC SUVs, although the order of the Kp values remained unchanged. The order of the Kp values agreed with that of the reported dermatological therapeutic potency of these drugs, although the order of their log P values for n-octanol/water systems showed a discrepancy. Our results indicate that the potency of steroid drugs in dermatological treatments depends to some extent on the Kp values of the drug, that is, the affinity of steroid drugs for PC bilayers influences their clinical potency, since potency is related to transdermal absorption.
authors.affiliation: Kyoto Pharmaceutical University, Misasagi, Kyoto, Japan. takegami@mb.kyoto-phu.ac.jp
authors.forename: Shigehiko
authors.initials: S
authors.lastname: Takegami
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kitamura
authors.forename: Takako
authors.initials: T
authors.lastname: Funakoshi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kitade
mesh_terms: D000465:Algorithms; D000893:Anti-Inflammatory Agents / Q000737:chemistry*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002784:Cholesterol / Q000737:chemistry*; D003879:Dermatologic Agents / Q000737:chemistry; D004337:Drug Carriers; D004339:Drug Compounding; D007202:Indicators and Reagents; D008567:Membranes, Artificial; D010316:Particle Size; D010713:Phosphatidylcholines / Q000737:chemistry*; D010758:Phosphorus / Q000032:analysis; D013056:Spectrophotometry, Ultraviolet; D013256:Steroids / Q000737:chemistry*
chemical_list: D000893:Anti-Inflammatory Agents; D003879:Dermatologic Agents; D004337:Drug Carriers; D007202:Indicators and Reagents; D008567:Membranes, Artificial; D010713:Phosphatidylcholines; D013256:Steroids; D010758:Phosphorus; D002784:Cholesterol