PMID- 18381488
OWN - NLM
STAT- MEDLINE
DCOM- 20080811
LR  - 20131121
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Linking)
VI  - 36
IP  - 7
DP  - 2008 Jul
TI  - Prediction of pharmacokinetic drug-drug interactions using human hepatocyte 
      suspension in plasma and cytochrome P450 phenotypic data. III. In vitro-in vivo 
      correlation with fluconazole.
PG  - 1261-6
LID - 10.1124/dmd.107.019000 [doi]
AB  - Whereas ketoconazole is often used to study the worst-case scenario for clinical 
      pharmacokinetic drug-drug interactions (DDIs) for drugs that are primarily 
      metabolized by CYP3A4, fluconazole is considered to be a moderate inhibitor of 
      CYP3A4, providing assessment of the moderate-case scenario of CYP3A-based DDIs. 
      Fluconazole is also a moderate inhibitor of CYP2C9 and CYP2C19. For predicting 
      clinical DDIs using conventional approaches, determining the in vivo inhibitor 
      concentration at the enzymatic site [I], a critical parameter, is still not 
      practical. In our previous study, a novel method involving hepatocyte suspension 
      in plasma was used to circumvent the need to determine the elusive [I] value. In 
      this study, the CYP1A2, 2C9, 2C19, 2D6, and 3A4 activities remaining in the 
      presence of fluconazole were determined in human hepatocytes suspended in human 
      plasma, covering a range of fluconazole clinical plasma concentrations (C(avg) 
      and C(max)). Because the protein-binding effect of fluconazole is expected to be 
      close to that in vivo, the inhibition observed in vitro will be similar to that 
      in vivo. This inhibition information was then applied to the cytochrome P450 
      (P450) phenotypic data to predict DDIs. Using the available P450 phenotypic 
      information on theophylline, tolbutamide, omeprazole, S-warfarin, phenytoin, 
      cyclosporine, and midazolam and that determined in this study for sirolimus and 
      tacrolimus, we found that the predictions for area under the curve increases for 
      most of these drugs in the presence of fluconazole were remarkably similar 
      (within 35%) to the observed clinical values. This study proves the general 
      applicability of our approach using human hepatocyte incubation in human plasma 
      to predict DDIs.
FAU - Lu, Chuang
AU  - Lu C
AD  - Drug Metabolism and Pharmacokinetics, Drug Safety and Disposition, Millennium 
      Pharmaceuticals, Inc., 40 Landsdowne St., Cambridge, MA 02139, USA. 
      chuang.lu@mpi.com
FAU - Berg, Cicely
AU  - Berg C
FAU - Prakash, Shimoga R
AU  - Prakash SR
FAU - Lee, Frank W
AU  - Lee FW
FAU - Balani, Suresh K
AU  - Balani SK
LA  - eng
PT  - Journal Article
DEP - 20080401
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Antifungal Agents)
RN  - 8VZV102JFY (Fluconazole)
SB  - IM
MH  - Antifungal Agents/blood/*pharmacokinetics
MH  - Area Under Curve
MH  - Drug Interactions
MH  - Fluconazole/blood/*pharmacokinetics
MH  - Hepatocytes/*drug effects/enzymology
MH  - Humans
EDAT- 2008/04/03 09:00
MHDA- 2008/08/12 09:00
CRDT- 2008/04/03 09:00
PHST- 2008/04/03 09:00 [pubmed]
PHST- 2008/08/12 09:00 [medline]
PHST- 2008/04/03 09:00 [entrez]
AID - dmd.107.019000 [pii]
AID - 10.1124/dmd.107.019000 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2008 Jul;36(7):1261-6. doi: 10.1124/dmd.107.019000. Epub 2008 
      Apr 1.