title: Identification of esterase involved in the metabolism of two corticosteroid soft drugs.
abstract: The soft drug approach is successful in obtaining high local therapeutic efficacy without systemic adverse effects, because soft drugs are designed to be bioconverted to inactive form by hydrolytic enzymes in systemic circulation. However, there is little information about the exact nature of these metabolic enzymes. In this study, the human enzymes for biotransformation of soft drugs were investigated. Loteprednol etabonate (LE) and etiprednol dicloacetate (ED) were designed from Δ1-cortienic acid (Δ1-CA), the inactive metabolite of prednisolone, by introducing two labile ester bonds to restore the corticosteroidal activity. We found that LE and ED were mainly deactivated in human plasma rather than the liver. Inactive monoesters were produced, but the second hydrolysis to Δ1-CA was much slower. ED was hydrolyzed 10 times faster than LE in plasma (t1/2=1.35±0.08, 12.07±0.52h respectively). Paraoxonase 1 that attached with high density lipoprotein (HDL) was found to be the major hydrolase for LE and ED in human plasma as demonstrated by enzyme inhibition and stimulation experiments and the hydrolysis in lipoproteins-rich plasma fractions. Human serum albumin (HSA) showed slight hydrolase activity against ED but not LE. LE was slowly hydrolyzed in liver (clearance: 0.21±0.04 and 2.41±0.13ml/h/kg in liver and plasma, respectively) but ED wasn't hydrolyzed at all, so LE has superior metabolism in two sites. The difficult diffusion of HDL into tissues from blood suggests the stable presence of LE at the administration site, while ED might be deactivated by its relatively rapid chemical hydrolysis and hydrolase activity of HSA, in the interstitial fluid of the administration tissue. Moreover, deactivation in plasma and strong protein binding (around 98%) minimize the adverse effects of LE and ED in the systemic circulation.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan. Electronic address: 143y2002@st.kumamoto-u.ac.jp.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Samir
authors.affiliation: Bodor Laboratories, Miami, FL 33137, USA; College of Pharmacy, University of Florida, Gainesville, FL 32611, USA. Electronic address: bodor@cop.ufl.edu.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Bodor
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan. Electronic address: iteruko@gpo.kumamoto-u.ac.jp.
authors.forename: Teruko
authors.initials: T
authors.lastname: Imai
mesh_terms: D000305:Adrenal Cortex Hormones / Q000097:blood / Q000378:metabolism*; D043303:Aryldialkylphosphatase / Q000378:metabolism*; D001624:Betamethasone Valerate / Q000097:blood / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D000069559:Loteprednol Etabonate / Q000097:blood / Q000378:metabolism*; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D008074:Lipoproteins; D012709:Serum Albumin; C450000:etiprednol dicloacetate; D001624:Betamethasone Valerate; D043303:Aryldialkylphosphatase; D000069559:Loteprednol Etabonate
keywords: Betamethasone valerate (PubChem CID: 57486087); Corticosteroids; EDTA trisodium (PubChem CID: 9008); Eserine (PubChem CID: 5983); Ethylene glycol (PubChem CID: 174); Etiprednol dicloacetate; Etiprednol dicloacetate (PubChem CID: 9935073); Glycine (PubChem CID: 750); HEPES (PubChem CID: 23821); Hydrolysis; Loteprednol etabonate; Loteprednol etabonate (PubChem CID: 444025); Paraoxon (PubChem CID: 9395); Paraoxonase 1; Soft drugs; Δ(1)-Cortienic acid (PubChem CID: 7092779)