PMID- 20536260
OWN - NLM
STAT- MEDLINE
DCOM- 20101124
LR  - 20220318
IS  - 1543-8392 (Electronic)
IS  - 1543-8384 (Print)
IS  - 1543-8384 (Linking)
VI  - 7
IP  - 4
DP  - 2010 Aug 2
TI  - Enabling the intestinal absorption of highly polar antiviral agents: ion-pair 
      facilitated membrane permeation of zanamivir heptyl ester and guanidino 
      oseltamivir.
PG  - 1223-34
LID - 10.1021/mp100050d [doi]
AB  - Antiviral drugs often suffer from poor intestinal permeability, preventing their 
      delivery via the oral route. The goal of this work was to enhance the intestinal 
      absorption of the low-permeability antiviral agents zanamivir heptyl ester (ZHE) 
      and guanidino oseltamivir (GO) utilizing an ion-pairing approach, as a critical 
      step toward making them oral drugs. The counterion 1-hydroxy-2-naphthoic acid 
      (HNAP) was utilized to enhance the lipophilicity and permeability of the highly 
      polar drugs. HNAP substantially increased the log P of the drugs by up to 3.7 log 
      units. Binding constants (K(11(aq))) of 388 M(-1) for ZHE-HNAP and 2.91 M(-1) for 
      GO-HNAP were obtained by applying a quasi-equilibrium transport model to 
      double-reciprocal plots of apparent octanol-buffer distribution coefficients 
      versus HNAP concentration. HNAP enhanced the apparent permeability (P(app)) of 
      both compounds across Caco-2 cell monolayers in a concentration-dependent manner, 
      as substantial P(app) (0.8-3.0 x 10(-6) cm/s) was observed in the presence of 
      6-24 mM HNAP, whereas no detectable transport was observed without counterion. 
      Consistent with a quasi-equilibrium transport model, a linear relationship with 
      slope near 1 was obtained from a log-log plot of Caco-2 P(app) versus HNAP 
      concentration, supporting the ion-pair mechanism behind the permeability 
      enhancement. In the rat jejunal perfusion assay, the addition of HNAP failed to 
      increase the effective permeability (P(eff)) of GO. However, the rat jejunal 
      permeability of ZHE was significantly enhanced by the addition of HNAP in a 
      concentration-dependent manner, from essentially zero without HNAP to 4.0 x 
      10(-5) cm/s with 10 mM HNAP, matching the P(eff) of the high-permeability 
      standard metoprolol. The success of ZHE-HNAP was explained by its >100-fold 
      stronger K(11(aq)) versus GO-HNAP, making ZHE-HNAP less prone to dissociation and 
      ion-exchange with competing endogenous anions and able to remain intact during 
      membrane permeation. Overall, this work presents a novel approach to enable the 
      oral delivery of highly polar antiviral drugs, and provides new insights into the 
      underlying mechanisms governing the success or failure of the ion-pairing 
      strategy to increase oral absorption.
FAU - Miller, Jonathan M
AU  - Miller JM
AD  - Center for Molecular Drug Targeting, Department of Pharmaceutical Sciences, 
      College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, USA.
FAU - Dahan, Arik
AU  - Dahan A
FAU - Gupta, Deepak
AU  - Gupta D
FAU - Varghese, Sheeba
AU  - Varghese S
FAU - Amidon, Gordon L
AU  - Amidon GL
LA  - eng
GR  - R01 GM037188/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Mol Pharm
JT  - Molecular pharmaceutics
JID - 101197791
RN  - 0 (Antiviral Agents)
RN  - 20O93L6F9H (Oseltamivir)
RN  - L6O3XI777I (Zanamivir)
SB  - IM
MH  - Animals
MH  - Antiviral Agents/*chemistry/*pharmacokinetics
MH  - Caco-2 Cells
MH  - Chromatography, High Pressure Liquid
MH  - Humans
MH  - In Vitro Techniques
MH  - Intestinal Absorption
MH  - Jejunum/metabolism
MH  - Magnetic Resonance Spectroscopy
MH  - Male
MH  - Oseltamivir/*chemistry/*pharmacokinetics
MH  - Rats
MH  - Rats, Wistar
MH  - Zanamivir/*chemistry/*pharmacokinetics
PMC - PMC3496398
MID - NIHMS414437
EDAT- 2010/06/12 06:00
MHDA- 2010/12/14 06:00
PMCR- 2012/11/13
CRDT- 2010/06/12 06:00
PHST- 2010/06/12 06:00 [entrez]
PHST- 2010/06/12 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
PHST- 2012/11/13 00:00 [pmc-release]
AID - 10.1021/mp100050d [doi]
PST - ppublish
SO  - Mol Pharm. 2010 Aug 2;7(4):1223-34. doi: 10.1021/mp100050d.