PMID- 26808419
OWN - NLM
STAT- MEDLINE
DCOM- 20171106
LR  - 20211204
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 81
IP  - 6
DP  - 2016 Jun
TI  - Scaling factors for the in vitro-in vivo extrapolation (IV-IVE) of renal drug and 
      xenobiotic glucuronidation clearance.
PG  - 1153-64
LID - 10.1111/bcp.12889 [doi]
AB  - AIM: To determine the scaling factors required for inclusion of renal drug 
      glucuronidation clearance in the prediction of total clearance via 
      glucuronidation (CLUGT ). METHODS: Microsomal protein per gram of kidney (MPPGK) 
      was determined for human 'mixed' kidney (n = 5) microsomes (MKM). The 
      glucuronidation activities of deferiprone (DEF), propofol (PRO) and zidovudine 
      (AZT) by MKM and paired cortical (KCM) and medullary (KMM) microsomes were 
      measured, along with the UGT 1A6, 1A9 and 2B7 protein contents of each enzyme 
      source. Unbound intrinsic clearances (CLint,u,UGT ) for PRO and morphine (MOR; 3- 
      and 6-) glucuronidation by MKM, human liver microsomes (HLM) and recombinant 
      UGT1A9 and 2B7 were additionally determined. Data were scaled using in vitro-in 
      vivo extrapolation (IV-IVE) approaches to assess the influence of renal 
      CLint,u,UGT on the prediction accuracy of the calculated CLUGT values of PRO and 
      MOR. RESULTS: MPPGK was 9.3 +/- 2.0 mg g(-1) (mean +/- SD). The respective rates of 
      DEF (UGT1A6), PRO (UGT1A9) and AZT (UGT2B7) glucuronidation by KCM were 1.4-, 
      5.2- and 10.5-fold higher than those for KMM. UGT 1A6, 1A9 and 2B7 were the only 
      enzymes expressed in kidney. Consistent with the activity data, the abundance of 
      each of these enzymes was greater in KCM than in KMM. The abundance of UGT1A9 in 
      MKM (61.3 pmol mg(-1) ) was 2.7 fold higher than that reported for HLM. 
      CONCLUSIONS: Scaled renal PRO glucuronidation CLint,u,UGT was double that of 
      liver. Renal CLint,u,UGT should be accounted for in the IV-IVE of UGT1A9 and 
      considered for UGT1A6 and 2B7 substrates.
CI  - (c) 2016 The British Pharmacological Society.
FAU - Knights, Kathleen M
AU  - Knights KM
AD  - Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, 
      School of Medicine, Flinders University, Adelaide, South Australia, Australia, 
      5001.
FAU - Spencer, Shane M
AU  - Spencer SM
AD  - Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, 
      School of Medicine, Flinders University, Adelaide, South Australia, Australia, 
      5001.
FAU - Fallon, John K
AU  - Fallon JK
AUID- ORCID: 0000-0003-1848-0121
AD  - Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of 
      North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.
FAU - Chau, Nuy
AU  - Chau N
AD  - Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, 
      School of Medicine, Flinders University, Adelaide, South Australia, Australia, 
      5001.
FAU - Smith, Philip C
AU  - Smith PC
AD  - Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of 
      North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.
FAU - Miners, John O
AU  - Miners JO
AD  - Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, 
      School of Medicine, Flinders University, Adelaide, South Australia, Australia, 
      5001.
LA  - eng
GR  - U10 CA180888/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20160314
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Proteins)
RN  - 0 (Pyridones)
RN  - 0 (UGT1A9 protein, human)
RN  - 2BTY8KH53L (Deferiprone)
RN  - 4B9XT59T7S (Zidovudine)
RN  - 76I7G6D29C (Morphine)
RN  - EC 2.4.1.- (UDP-glucuronosyltransferase, UGT1A6)
RN  - EC 2.4.1.- (UGT2B7 protein, human)
RN  - EC 2.4.1.17 (Glucuronosyltransferase)
RN  - EC 2.4.1.17 (UDP-Glucuronosyltransferase 1A9)
RN  - YI7VU623SF (Propofol)
SB  - IM
MH  - Deferiprone
MH  - Glucuronosyltransferase/metabolism
MH  - Kidney/enzymology
MH  - Microsomes/enzymology
MH  - Microsomes, Liver/enzymology
MH  - Morphine/pharmacokinetics
MH  - Propofol/*pharmacokinetics
MH  - Proteins/metabolism
MH  - Pyridones/*pharmacokinetics
MH  - UDP-Glucuronosyltransferase 1A9
MH  - Zidovudine/*pharmacokinetics
PMC - PMC4876189
OTO - NOTNLM
OT  - UGT1A9
OT  - UGT2B7
OT  - human kidney microsomes
OT  - microsomal yield
OT  - renal drug glucuronidation clearance
EDAT- 2016/01/26 06:00
MHDA- 2017/11/07 06:00
PMCR- 2017/06/01
CRDT- 2016/01/26 06:00
PHST- 2015/11/04 00:00 [received]
PHST- 2016/01/19 00:00 [revised]
PHST- 2016/01/21 00:00 [accepted]
PHST- 2016/01/26 06:00 [entrez]
PHST- 2016/01/26 06:00 [pubmed]
PHST- 2017/11/07 06:00 [medline]
PHST- 2017/06/01 00:00 [pmc-release]
AID - BCP12889 [pii]
AID - 10.1111/bcp.12889 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2016 Jun;81(6):1153-64. doi: 10.1111/bcp.12889. Epub 2016 
      Mar 14.