Author: Mitsunori Kato ; Izumi Fujimori ; Toshihiko Ikeda ; Osamu Okazaki ; Yasushi Yoshigae ; Kazuishi Kubota ; Takashi Izumi ; Tomoko Ishizuka ; Chisa Noji-Sakikawa ; Atsushi Kurihara ; Motoko Saito

Olmesartan medoxomil (OM) is a prodrug type angiotensin II type 1 receptor antagonist widely prescribed as an antihypertensive agent. Herein, we describe the identification and characterization of the OM bioactivating enzyme that hydrolyzes the prodrug and converts to its pharmacologically active metabolite olmesartan in human liver and intestine. The protein was purified from human liver cytosol by successive column chromatography and was identified by mass spectrometry to be a carboxymethylenebutenolidase (CMBL) homolog. Human CMBL, whose endogenous function has still not been reported, is a human homolog of Pseudomonas dienelactone hydrolase involved in the bacterial halocatechol degradation pathway. The ubiquitous expression of human CMBL gene transcript in various tissues was observed. The recombinant human CMBL expressed in mammalian cells was clearly shown to activate OM. By comparing the enzyme kinetics and chemical inhibition properties between the recombinant protein and human tissue preparations, CMBL was demonstrated to be the primary OM bioactivating enzyme in the liver and intestine. The recombinant CMBL also converted other prodrugs having the same ester structure as OM, faropenem medoxomil and lenampicillin, to their active metabolites. CMBL exhibited a unique sensitivity to chemical inhibitors, thus, being distinguishable from other known esterases. Site-directed mutagenesis on the putative active residue Cys(132) of the recombinant CMBL caused a drastic reduction of the OM-hydrolyzing activity. We report for the first time that CMBL serves as a key enzyme in the bioactivation of OM, hydrolyzing the ester bond of the prodrug type xenobiotics.

01 Feb 2010·Journal of Pharmaceutical SciencesQ3 · MEDICINE

Kinetic assessment of luminal degradation of orally effective prodrugs for rational drug development

Q3 · MEDICINE

Article

Author: Mizuma, Takashi

Although prodrugging (prodrug derivatization) is a powerful technique for improving the pharmacokinetic characteristics of drugs, the intestinal pharmacokinetics of prodrugs has yet to be elucidated fully. A previous article reported the kinetic requirement of prodrugs to overcome membrane barriers. In the present article, the luminal degradation of prodrugs was kinetically assessed to understand crucial factors in the intestinal absorption of prodrugs and to show a rational development procedure. A kinetic model equation involving luminal degradation clearance (CL(deg)) was derived, and CL(deg) was estimated according to the equation with in vitro and in vivo reported data of two kinds of ampicillin prodrugs (lenampicillin and pivampicillin) and one acyclovir prodrug (valacyclovir). For lenampicillin ((2,2-dimethyl-1-oxopropoxy)methyl ester derivative), CL(deg) was approximately 1.7 times as large as absorption clearance (CL(abs)), whereas for pivampicillin ((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester derivative), CL(deg) was approximately one tenth of CL(abs). For valacyclovir (acyclovir prodrug), CL(deg) was negligible. These results indicate that not only membrane permeability but also luminal stability should be assessed for the rational development of orally effective prodrugs, and that luminal stabilization can improve the intestinal absorption of prodrugs. A procedure was proposed to develop orally effective prodrugs considered for luminal degradation as well as membrane permeability.

01 Jan 2009·Folia Pharmacologica Japonica

Impact of intestinal metabolism on drug development

Review

Author: Mizuma, Takashi

A review on the basic study for intestinal metabolism of per Os drugs in human, discussing oxidation of drugs as intestinal first-pass metabolism through CYP3A, conjugate metabolism by SULT1A3 and glucuronidation via UGT1A8 or UGT1A10 as second-pass metabolismFrom view of drug delivery system, intestinal metabolism is promising for preprodrug development due to alternation chem. substance to drug like lenampicillin to ampicillin.

100 Deals associated with Lenampicillin hydrochloride

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Bacterial Infections	CN	Shandong Lukang Pharmaceutical Co., Ltd.	17 Mar 2004

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