PMID- 17207946
OWN - NLM
STAT- MEDLINE
DCOM- 20070815
LR  - 20181201
IS  - 0378-5173 (Print)
IS  - 1873-3476 (Electronic)
IS  - 0378-5173 (Linking)
VI  - 336
IP  - 2
DP  - 2007 May 24
TI  - Intestinal absorption of novel-dipeptide prodrugs of saquinavir in rats.
PG  - 233-40
AB  - Saquinavir (SQV) was the first human immuno-virus-1 (HIV-1) protease inhibitor 
      approved by FDA. However, P-glycoprotein (P-gp), an efflux pump limits its oral 
      and brain bioavailabilities. The objective of this study is to investigate 
      whether prodrug modification of SQV to dipeptide prodrugs 
      Valine-Valine-Saquinavir (Val-Val-SQV) and Glycine-Valine-Saquinavir 
      (Gly-Val-SQV) targeting intestinal peptide transporter can enhance intestinal 
      permeability of SQV by circumventing P-gp mediated efflux. Single pass intestinal 
      perfusion experiments in rat jejunum were performed to calculate the absorption 
      rate constant and intestinal permeability of SQV, Val-Val-SQV and Gly-Val-SQV. 
      Equimolar concentration (25 microM) of SQV, Val-Val-SQV and Gly-Val-SQV were 
      employed in the perfusion studies. Perfusion experiments were also carried out in 
      the presence of cyclosporine (10 microM) and glycyl-sarcosine (20 mM). Absorption 
      rate constants in rat jejunum (ka) for SQV, Val-Val-SQV and Gly-Val-SQV were 
      found to be 14.1+/-3.4x10(-3), 65.8+/-4.3x10(-3), and 25.6+/-5.7x10(-3) min(-1), 
      respectively. Enhanced absorption of Val-Val-SQV and Gly-Val-SQV relative to SQV 
      can be attributed to their translocation by the peptide transporter in the 
      jejunum. Significant permeability enhancement of SQV across rat jejunum was 
      observed in the presence of cyclosporine 10 microM (P-gp inhibitor). However, 
      permeability of Val-Val-SQV was unchanged in the presence of cyclosporine 
      suggesting lack of any interaction of the prodrug with efflux pump. Intestinal 
      absorption of Val-Val-SQV was significantly inhibited in the presence of gly-sar 
      indicating the involvement of peptide transporter in intestinal absorption. In 
      conclusion, peptide transporter targeted prodrug modification of P-gp substrates 
      could lead to shielding of these drug molecules from efflux pumps.
FAU - Jain, Ritesh
AU  - Jain R
AD  - Division of Pharmaceutical Sciences, School of Pharmacy, University of 
      Missouri-Kansas City, MO 64110-2499, USA.
FAU - Duvvuri, Sridhar
AU  - Duvvuri S
FAU - Kansara, Viral
AU  - Kansara V
FAU - Mandava, Nanda Kishore
AU  - Mandava NK
FAU - Mitra, Ashim K
AU  - Mitra AK
LA  - eng
GR  - R01 GM064320/GM/NIGMS NIH HHS/United States
GR  - R01 GM064320-03/GM/NIGMS NIH HHS/United States
GR  - GM 64320-03/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20061203
PL  - Netherlands
TA  - Int J Pharm
JT  - International journal of pharmaceutics
JID - 7804127
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (HIV Protease Inhibitors)
RN  - 0 (Prodrugs)
RN  - 0 (glycine-valine-saquinavir)
RN  - 0 (valine-valine-saquinavir)
RN  - L3JE09KZ2F (Saquinavir)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
MH  - Animals
MH  - Biological Availability
MH  - Biological Transport
MH  - Drug Stability
MH  - HIV Protease Inhibitors/chemical synthesis/chemistry/*pharmacokinetics
MH  - Intestinal Absorption
MH  - Jejunum/metabolism
MH  - Male
MH  - Permeability
MH  - Prodrugs/chemical synthesis/chemistry/*pharmacokinetics
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Saquinavir/*analogs & derivatives/chemical synthesis/chemistry/*pharmacokinetics
PMC - PMC3166959
MID - NIHMS23895
EDAT- 2007/01/09 09:00
MHDA- 2007/08/19 09:00
PMCR- 2011/09/06
CRDT- 2007/01/09 09:00
PHST- 2006/07/03 00:00 [received]
PHST- 2006/11/21 00:00 [revised]
PHST- 2006/11/27 00:00 [accepted]
PHST- 2007/01/09 09:00 [pubmed]
PHST- 2007/08/19 09:00 [medline]
PHST- 2007/01/09 09:00 [entrez]
PHST- 2011/09/06 00:00 [pmc-release]
AID - S0378-5173(06)01036-2 [pii]
AID - 10.1016/j.ijpharm.2006.11.058 [doi]
PST - ppublish
SO  - Int J Pharm. 2007 May 24;336(2):233-40. doi: 10.1016/j.ijpharm.2006.11.058. Epub 
      2006 Dec 3.