title: A novel strategy for ADME screening of prodrugs: combined use of serum and hepatocytes to integrate bioactivation and clearance, and predict exposure to both active and prodrug to the systemic circulation.
abstract: Common strategies to optimize prodrugs use either in vitro or rodent in vivo approaches, which do not consider elimination pathways that do not result in the generation of the desired product or might be misleading because of species differences, respectively. As a step forward, we have incorporated a novel application of hepatocytes into our prodrug optimization strategy to increase the bioavailability of a poorly soluble drug candidate by attaching a charged ester linker. The model involves the incubation of hepatocytes from multiple species in serum-containing medium to mimic formation as well as simultaneous metabolism of both prodrug and active drug. Using this strategy, a correlation between the in vitro AUC and the AUC after intravenous administration was obtained for active drug formation in several species. Moreover, hepatocytes correctly predicted the likelihood of undesired exposure with nonhydrolyzed prodrug. This novel approach enabled us to identify several prodrugs, which showed improved exposure over a wide dose range. Furthermore, a strategy was developed resulting in a decision tree that can be used to determine the applicability of the hepatocyte model in the screening process.
authors.affiliation: Grünenthal GmbH, Aachen, 52078, Germany.
authors.forename: Edmund
authors.initials: E
authors.lastname: Hoppe
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Hewitt
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Buchstaller
authors.forename: Hans-Michael
authors.initials: HM
authors.lastname: Eggenweiler
authors.forename: Christian
authors.initials: C
authors.lastname: Sirrenberg
authors.forename: Astrid
authors.initials: A
authors.lastname: Zimmermann
authors.forename: Joachim
authors.initials: J
authors.lastname: März
authors.forename: Harry
authors.initials: H
authors.lastname: Schwartz
authors.forename: Christoph
authors.initials: C
authors.lastname: Saal
authors.forename: Michael
authors.initials: M
authors.lastname: Meyring
authors.forename: Stefan
authors.initials: S
authors.lastname: Hecht
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D004285:Dogs; D004952:Esters / Q000737:chemistry; D005260:Female; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D044967:Serum / Q000378:metabolism*; D012995:Solubility
chemical_list: D004952:Esters; D004364:Pharmaceutical Preparations; D011355:Prodrugs
keywords: absorption; active drug; bioavailability; exposure; hepatocytes; in vitro models; prodrug; screening strategy; serum