PMID- 20201776
OWN - NLM
STAT- MEDLINE
DCOM- 20100609
LR  - 20201209
IS  - 1874-0758 (Electronic)
IS  - 1872-3128 (Linking)
VI  - 4
IP  - 1
DP  - 2010 Jan
TI  - Impact of ritonavir, atazanavir and their combination on the CYP3A4 induction 
      potential of efavirenz in primary human hepatocytes.
PG  - 45-50
AB  - Currently used combinations of anti-HIV drugs, known as Highly Active 
      Antiretroviral Therapy (HAART), have considerably reduced the mortality in 
      patients with AIDS. However, HAART medications such as efavirenz (EFV), 
      atazanavir (ATV) and ritonavir (RTV) often cause adverse drug-drug interactions 
      (DDIs) that result from changes in the expression and activity of drug 
      metabolizing enzymes. Since EFV is most commonly used with ATV and RTV, the known 
      CYP inhibitors, we evaluated the effects of combinations of these agents on the 
      CYP3A4 induction by EFV. We determined the induction of CYP3A4 by EFV, RTV, ATV, 
      EFV+RTV, EFV+ATV, EFV+RTV+ATV and rifampicin (RIF) employing primary human 
      hepatocytes from 3 donors. Also, concentration dependent activation of human 
      Pregnane X-receptor (hPXR) which is key transcriptional regulator of CYP3A4 by 
      EFV, RIF and RTV was estimated in transiently transfected LS180 cells. CYP3A4 
      activity (testosterone-6beta-hydroxylation) was induced by EFV (3 fold) and RIF 
      (4 fold), but was significantly suppressed in the presence of RTV and ATV. All 
      treatments significantly induced the CYP3A4 transcripts (3-25 fold) as 
      quantitated by RT-PCR. hPXR activation data in LS180 cells were consistent with 
      the induction of transcripts and the estimated EC(50) values were 0.87 microM, 
      0.44 microM and 3.7 microM for RIF, RTV and EFV, respectively. However, in 
      primary hepatocytes the net effect was suppression of EFV mediated CYP3A4 
      induction by RTV and ATV. This observation corresponds to the clinical 
      observations of attenuated CYP3A4 induction by EFV induction in the presence of 
      RTV and other protease inhibitors (PIs). Our results underscore the limitation of 
      transcriptional activation assays in predicting the net outcome for compounds 
      that exhibit complex interactions resulting from induction and inhibition of CYP 
      enzymes.
FAU - Mugundu, Ganesh M
AU  - Mugundu GM
AD  - Division of Pharmaceutical Sciences, College of Pharmacy, University of 
      Cincinnati Medical Center, Cincinnati, Ohio 45267-0004, USA.
FAU - Hariparsad, Niresh
AU  - Hariparsad N
FAU - Desai, Pankaj B
AU  - Desai PB
LA  - eng
PT  - Journal Article
PL  - United Arab Emirates
TA  - Drug Metab Lett
JT  - Drug metabolism letters
JID - 101313587
RN  - 0 (Alkynes)
RN  - 0 (Anti-HIV Agents)
RN  - 0 (Benzoxazines)
RN  - 0 (Cyclopropanes)
RN  - 0 (Oligopeptides)
RN  - 0 (Pregnane X Receptor)
RN  - 0 (Pyridines)
RN  - 0 (Receptors, Steroid)
RN  - 4MT4VIE29P (Atazanavir Sulfate)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - EC 1.14.14.55 (CYP3A4 protein, human)
RN  - JE6H2O27P8 (efavirenz)
RN  - O3J8G9O825 (Ritonavir)
SB  - IM
MH  - Alkynes
MH  - Anti-HIV Agents/administration & dosage/pharmacology
MH  - Atazanavir Sulfate
MH  - Benzoxazines/administration & dosage/*pharmacology
MH  - Cell Line, Tumor
MH  - Cyclopropanes
MH  - Cytochrome P-450 CYP3A/biosynthesis/*drug effects/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Drug Interactions
MH  - Drug Therapy, Combination
MH  - Enzyme Induction/drug effects
MH  - Hepatocytes/drug effects/metabolism
MH  - Humans
MH  - Oligopeptides/administration & dosage/*pharmacology
MH  - Pregnane X Receptor
MH  - Pyridines/administration & dosage/*pharmacology
MH  - Receptors, Steroid/drug effects/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Ritonavir/administration & dosage/*pharmacology
MH  - Transfection
EDAT- 2010/03/06 06:00
MHDA- 2010/06/10 06:00
CRDT- 2010/03/06 06:00
PHST- 2009/07/09 00:00 [received]
PHST- 2009/10/04 00:00 [accepted]
PHST- 2010/03/06 06:00 [entrez]
PHST- 2010/03/06 06:00 [pubmed]
PHST- 2010/06/10 06:00 [medline]
AID - BSP/DML/E-Pub/00027 [pii]
AID - 10.2174/187231210790980453 [doi]
PST - ppublish
SO  - Drug Metab Lett. 2010 Jan;4(1):45-50. doi: 10.2174/187231210790980453.