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Divalent metals and pH alter raltegravir disposition in vitro
Darren M Moss1, Marco Siccardi, Matthew Murphy
1Department of Molecular and Clinical Pharmacology University of Liverpool, Liverpool, United Kingdom.
Antimicrobial Agents and Chemotherapy
|March 28, 2012
Summary
Raltegravir
Area of Science:
- Pharmacology and Drug Metabolism
Background:
- Raltegravir exhibits significant pharmacokinetic variability in patients.
- Gastrointestinal pH and interactions with divalent metals are suspected contributing factors.
Purpose of the Study:
- To investigate the in vitro solubility, lipophilicity, pKa, and permeativity of raltegravir.
- To elucidate interactions with omeprazole, antacids, and food, which affect gastric pH.
Main Methods:
- Solubility, lipophilicity, and pKa were determined using standard laboratory techniques.
- Cellular permeativity and accumulation were assessed using Caco-2 cell monolayers under varying pH and metal ion conditions.
- Samples were analyzed via liquid chromatography-tandem mass spectroscopy (LC-MS/MS) and scintillation counting.
Main Results:
- Raltegravir solubility decreased below pH 6.6.
- Lipophilicity and cellular permeativity were pH-dependent, with reduced permeativity at higher pH.
- Magnesium and calcium ions reduced raltegravir permeativity, while omeprazole had no significant effect.
Conclusions:
- Gastrointestinal pH and polyvalent metal ions significantly influence raltegravir's pharmacokinetic properties.
- These findings explain patient variability in raltegravir exposure and justify further investigation into multivitamin interactions.
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