PMID- 18006646
OWN - NLM
STAT- MEDLINE
DCOM- 20080221
LR  - 20131121
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Linking)
VI  - 36
IP  - 2
DP  - 2008 Feb
TI  - Biosynthesis of drug metabolites using microbes in hollow fiber cartridge 
      reactors: case study of diclofenac metabolism by Actinoplanes species.
PG  - 234-40
AB  - Fungal and bacterial microbes are known to mimic mammalian cytochrome P450 
      metabolism. Traditionally, microbial biotransformation screening and small 
      scale-ups (<1 liter) are performed in shake-flask reactors. An alternative 
      approach is the use of hollow fiber cartridge (HFC) reactors. The performance of 
      HFC reactors is compared with shake-flask reactors using diclofenac as a model 
      substrate. Actinoplanes sp. (American Type Culture Collection 53771) in a 
      shake-flask reactor hydroxylated diclofenac (50 microM) with 100% turnover in 
      less than 5 h. A scaled-up production resulted in the formation of 4'-hydroxy 
      (169 mg, 54% yield), 5-hydroxy (42 mg, 13% yield), and 4',5-dihydroxy (25 mg, 
      7.7% yield) metabolites. HFC reactors with Teflon, polysulfone, and cellulose 
      membranes were screened for nonspecific binding of diclofenac. Concentration-time 
      profiles for turnover of 50 to 2000 microM diclofenac by Actinoplanes sp. were 
      then determined at 22 and 30 degrees C in an HFC reactor. Cellulose-based HFC 
      reactors exhibited the lowest nonspecific binding (87% of 50 microM diclofenac 
      remaining after 5 h) and offered the best conditions for its biotransformation 
      (100% conversion; < 5 h at 30 degrees C at 50 microM; 25 h at 500 microM). The 
      time profile for substrate turnover was equivalent in both a cellulose membrane 
      HFC reactor and shake-flask reactor. Two cellulose membrane HFC reactors were 
      also tested to evaluate the reusability of the cartridges for diclofenac 
      metabolism (50 microM, 22 degrees C, 15 h; 500 microM, 30 degrees C, 36 h). Up to 
      seven reaction cycles with intermediate wash cycles were tested. At least 98% 
      conversion was observed in each reaction cycle at both diclofenac concentrations.
FAU - Osorio-Lozada, Antonio
AU  - Osorio-Lozada A
AD  - Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, California 
      91320, USA.
FAU - Surapaneni, Sekhar
AU  - Surapaneni S
FAU - Skiles, Gary L
AU  - Skiles GL
FAU - Subramanian, Raju
AU  - Subramanian R
LA  - eng
PT  - Journal Article
DEP - 20071115
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 144O8QL0L1 (Diclofenac)
SB  - IM
MH  - Actinobacteria/*metabolism
MH  - Anti-Inflammatory Agents, Non-Steroidal/*metabolism
MH  - *Bioreactors
MH  - Biotransformation
MH  - Diclofenac/*metabolism
MH  - Fungi/metabolism
MH  - Hydroxylation
EDAT- 2007/11/17 09:00
MHDA- 2008/02/22 09:00
CRDT- 2007/11/17 09:00
PHST- 2007/11/17 09:00 [pubmed]
PHST- 2008/02/22 09:00 [medline]
PHST- 2007/11/17 09:00 [entrez]
AID - dmd.107.019323 [pii]
AID - 10.1124/dmd.107.019323 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2008 Feb;36(2):234-40. doi: 10.1124/dmd.107.019323. Epub 2007 
      Nov 15.