Abstract
<p><strong>Objective: </strong>To develop and validate simple, sensitive and selective ultra-performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS) method for quantification of rifampicin (RIF) in rat plasma and its application to pharmacokinetics study.</p><p><strong>Methods: </strong>Precipitation method was used for the extraction of plasma samples, an aliquot of 25 µl plasma samples was extracted using acetonitrile precipitation technique. Chromatographic separation was performed usingWaters Acquity<sup>TM</sup>UPLC columns, BEH C18 (50 mm× 2.1 mm, 1.7 µm) by a gradient mixture of acetonitrile and water (both containing 0.1 % formic acid) as a mobile phase at the flow rate of 0.7 ml/min.The analyte was protonated in the positive ESI (electrospray ionization interface) and detected in MRM (multiple reactions monitoring) modes using the transition m/z 308.60-455.30.</p><p><strong>Results: </strong>The method had a short chromatography run time of 1.8 min with improved sensitivity over existing methods. Calibration curves been linear over the wide range of 1.97-5047.00 ng/ml. The between and within-batch precision and accuracy of the method was determined by using 4 quality control samples; the highest %CV observed was10.11. The mean recovery values are 74.26, 82.77 and 101.73 at low, medium and high-quality control levels; respectively.</p><p><strong>Conclusion: </strong>It was concluded that the developed and validated UPLC-MS/MS method was sensitive,specific, precise, linear, and rapid. Therefore, the method can be used for quantification of RIFin rat plasma with various advantages over the reported methods. RIF is widely recommended by US-FDAguidance for industry on drug interaction studies and the developed method can be used to explore drug interaction studies in drug discovery and development.</p>
Highlights
RIF is a major antibacterial drug used for the treatment of tuberculosis, leprosy, some types of osteomyelitis and endocarditis, etc
Apart from this RIF is widely used for many drug-drug interaction (DDI) studies as an established inducer of multiple CYP enzymes (CYP2C8, 2C9, 2C19, 3A4; reported fold induction in enzyme activities are 2-4, 3.7, 20 and 4-31, respectively), transporters, and an inhibitor of the uptake transporter OATP1B1 and may inhibit the uptake of investigational drug that is a substrate of OATP1B1 [2-4]
To evaluate drug-herb interaction (DHI) studies using RIF, where an isolated active herbal constituent is not available and most of the marketed herbal products were available as amixture or aqueous extract in powder form and evaluating DHI studies in such cases is a very difficult task because no isolated fraction is available for bioanalytical quantification
Summary
RIF is a major antibacterial drug used for the treatment of tuberculosis, leprosy, some types of osteomyelitis and endocarditis, etc. To evaluate drug-herb interaction (DHI) studies using RIF, where an isolated active herbal constituent is not available and most of the marketed herbal products were available as amixture or aqueous extract in powder form and evaluating DHI studies in such cases is a very difficult task because no isolated fraction is available for bioanalytical quantification In such scenario, the only option remained is to plan the drug-herb interaction studies using RIF in vivo pharmacokinetics studies in animals and thereby quantification of RIF from plasma samples and the outcomes of the studies will be correlated with CYP inhibition/induction potential of concurrently administered herb drugs on the pharmacokinetics of RIF.As reported, CYP3A4 is the most abundant cytochrome P450 enzyme expressed in the liver and small intestine and plays a crucial role in metabolism and detoxification of xenobiotics and endobiotics. The expression levels of CYP3A4 vary widely among individual [6,7]
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