Simultaneous LC-MS/MS Determination of Racemic Warfarin and Etravirine in Rat Plasma and Its Application in Pharmacokinetic Studies
| Autor: | Jyothy John, Keila Robinson, Cyril V. Abobo, Mathew John, Jason Caballero, Dong Liang, Jing Ma |
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| Rok vydání: | 2012 |
| Předmět: |
Drug
Prothrombin time CYP3A4 medicine.diagnostic_test business.industry media_common.quotation_subject 010401 analytical chemistry Warfarin Etravirine Pharmacology 030226 pharmacology & pharmacy 01 natural sciences 3. Good health 0104 chemical sciences 03 medical and health sciences 0302 clinical medicine Therapeutic index Pharmacokinetics medicine business CYP2C9 medicine.drug media_common |
| Zdroj: | Tandem Mass Spectrometry-Applications and Principles |
| DOI: | 10.5772/32204 |
| Popis: | Warfarin, one of the most commonly used oral anticoagulant in the US and across the globe, is a drug of choice for millions. It’s a unique drug of its kind due to the multiple pharmacological and pharmacokinetic properties. The posology of warfarin cannot be generalized. Having the right dose for the right patient makes this drug follow a pattern that is unique among the lot. Warfarin has a high interpatient variability (Min-Jung Kwon et al., 2009) and narrow therapeutic index which requires continuous monitoring of its plasma concentration, the prothrombin time and the international normalized ratio followed by a dosage adjustment. Warfarin in pure form exists as a racemic mixture consisting of equal amounts of R and S enantiomers (Porter et al., 1986). The S enantiomer is more potent than the R form (Breckenridge et al., 1974). Warfarin is highly metabolized in the body in a stereo specific pathway catalyzed by cytochrome P450. R-warfarin is metabolized primarily by CYP1A2 to 6and 8-hydroxy warfarin, and by CYP3A4 to 10-hydroxy warfarin, while Swarfarin is metabolized primarily by CYP2C9 to 7-hydroxy warfarin (Kaminsky and Zhang., 1997). The properties of warfarin, such as narrow therapeutic index, high protein binding, CYP dependent metabolism and a very high elimination half life render to be prone to many drug interactions (Chan et al., 2009). Elimination half life of warfarin is relatively long (10-16 hours in animals and 40-46 hours in humans), causing a dramatic increase in the anticoagulant effect upon concomitant administration of warfarin with other drugs causing drug-drug interactions (Alexander and Areg et al., 2009). Etravirine is the first drug in the second generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV/AIDS. The drug was recently marketed for the treatment of HIV infection. It is of great advantage in combination with other antiretrovirals in the treatment of patients who are on this regimen for a considerable period of time. (Martha Boffito et al., 2009). Etravirine is highly bound to plasma proteins and is primarily metabolized by CYP450; 3A4, 2C9 and 2C19 iso-enzymes. Potential drug interactions of warfarin and etravirine are expected due to their high protein binding and similar hepatic metabolic characteristics. For most antiretrovirals it’s critical that drug concentrations are maintained above the suggested minimum effective concentration throughout the dosing interval. Suboptimal antiretroviral exposure may permit viral replication and predispose to |
| Databáze: | OpenAIRE |
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