PT  - JOURNAL ARTICLE
AU  - Haruka Nishimuta
AU  - J. Brian Houston
AU  - Aleksandra Galetin
TI  - Hepatic, Intestinal, Renal and Plasma Hydrolysis of Prodrugs in Human, Cynomolgus Monkey, Dog and Rat - Implications for In Vitro-In Vivo Extrapolation of Clearance of Prodrugs
AID  - 10.1124/dmd.114.057372
DP  - 2014 Jul 03
TA  - Drug Metabolism and Disposition
PG  - dmd.114.057372
4099  - http://dmd.aspetjournals.org/content/early/2014/07/02/dmd.114.057372.short
4100  - http://dmd.aspetjournals.org/content/early/2014/07/02/dmd.114.057372.full
AB  - Hydrolysis plays an important role in metabolic activation of prodrugs. In the current study, species and in vitro system differences in hepatic and extrahepatic hydrolysis were investigated for 11 prodrugs. Ten prodrugs in the dataset are predominantly hydrolyzed by carboxylesterases (CES), whereas olmesartan medoxomil is also metabolized by carboxymethylenebutenolidase (CMBL) and paraoxonase. Metabolic stabilities were assessed in cryopreserved hepatocytes, liver S9 (LS9), intestinal S9 (IS9), kidney S9 (KS9) and plasma from human, monkey, dog and rat. Of all the preclinical species investigated, monkey hydrolysis CLint,hepatocytes were the most comparable to human hepatocyte data. Perindopril and candesartan cilexetil showed the lowest and highest CLint,hepatocytes, respectively regardless of the species investigated. Scaled hydrolysis CLint,LS9 were generally higher than CLint,hepatocytes in all species investigated, with the exception of dog. In the case of human and dog intestinal S9, hydrolysis CLint could not be obtained for CES1 substrates, whereas hydrolysis for CES2 and CMBL substrates was detected in IS9 and KS9 from all species. Pronounced species differences were observed in plasma; hydrolysis of CES substrates was only evident in rat. Predictability of human CLint,h was assessed for 8 CES1 substrates using hepatocytes and LS9; extrahepatic hydrolysis was not considered due to high stability of these prodrugs in intestinal and kidney S9. On average, predicted oral CLint,h from hepatocyte data represented 20% of the observed value; the under-prediction was pronounced for high clearance prodrugs, consistent with predictability of P450/conjugation clearance from this system. Prediction bias was less apparent with LS9, in particular for high clearance prodrugs, highlighting the application of this in vitro system for investigation of prodrugs.