Computer-Assisted HPLC Method Development for Determination of Tolmetin and Possible Kinetic Modulators of Its Oxidative Metabolism in Vivo

Abstract

Following administration of the acidic drug tolmetin (TOL) anaphylactic reactions occurred, which have been hypothesized to be related to the formation of reactive acyl glucuronides. Recently, glutathione adducts have been detected upon incubation of TOL with human liver microsomal preparations, which proved that oxidative activation might also be a pathway of formation of reactive-possibly toxic-glutathione metabolites of TOL. The aim of this work was to develop a new and robust HPLC method to investigate the in vivo effect of 2 coadministered drugs/nutritional supplements on the kinetics of TOL in rats (cimetidine; CIM) known to be a potent inhibitor of CYP3A4, an enzyme that catalyzes the oxidative metabolism and Quercetin; and QUE which induces UGT1A6, an enzyme involved in glucuronidation of acidic drugs. DryLab Ò , a computer simulation software package, was used to assist in the development and optimization of the HPLC method used for separation of TOL and the two potential kinetic modulators together with three potential internal standards (zomepirac, carvedilol and fexofenadine). The method was validated in biological samples obtained from rats. Non-compartmental pharmacokinetic analysis of data obtained from plasma and rat liver tissue showed significantly higher concentrations of TOL in the presence of CIM; and significantly longer elimination halflife lives in presence of QUE, which implies that drugs or food components interacting with CYP3A4 cause alteration in the metabolic oxidative biotransformation of TOL in vivo leading to accumulation of TOL in the body through a decrease of its clearance. These findings might account for to the side-effects associated with TOL when co-administered with such kinetic modulators.

Green Assay of Tolmetin Sodium Using Solid Contact Potentiometric Sensor Doped with Ionophore and Supported with Docking Study: Application to Human Plasma and Pharmaceutical Formulations

“…Satisfactory % recoveries with RSD values were obtained, indicating the high selectivity of the proposed sensor. The results were statistically compared with those obtained by the reported HPLC method, 9 and t and F values were calculated using Student's t-test F-test at a 95% confidence level (Table IV). The proposed method shows no significant difference from the reported HPLC method because the calculated t and F values are less than the tabulated ones (Table IV).…”

“…Furthermore, the plasma drug concentration should be monitored closely, especially in patients with comorbidities. 2,4 TOL was assayed by different spectrophotometric, 5,6 HPLC, [7][8][9][10][11] UPLC-MS/MS, 12 fluorometric, 13 polarographic, 14 and stripping voltametric 15 methods in various matrices with the lack of a potentiometric ion selective electrode (ISE) for its assay in literature. The reported methods involved sample preparation, which contributes significantly to the variance and method confidence of the results.…”

Determination of the design space of the HPLC analysis of water-soluble vitamins

“…One of the most widely used softwares in defining an HPLC method design space nowadays is DryLab®. The software predicted resolution maps comprise mathematical calculations related to basic work of Snyder, Dolan, and Molnár and as well on the solvophobic theory, which has been studied and explained in details by Horváth, Melander, and Molnár decades ago .…”

Predictability of Enantiomeric Chromatographic Behavior on Various Chiral Stationary Phases Using Typical Reversed Phase Modeling Software

“…On the other hand, computer‐assisted HPLC method development has received much attention since late 1970s, especially in the pharmaceutical industry in order to save time and resources; furthermore, it achieves a robust analytical method. One of the most commonly used computer programs is DryLab, which has many applications in the reversed phase mode . Its predictions are based on mathematical calculations of the solvophobic theory, which has been studied and explained in detail by Horváth et al In solvophobic theory, the nature of both the stationary phase and the mobile phase are important for prediction of retention …”

“…One of the most commonly used computer programs is DryLab, which has many applications in the reversed phase mode. [9][10][11][12][13][14][15][16][17] Its predictions are based on mathematical calculations of the solvophobic theory, which has been studied and explained in detail by Horváth et al [18][19][20] In solvophobic theory, the nature of both the stationary phase and the mobile phase are important for prediction of retention. 21 The aim of this study is to use DryLab ® to investigate the predictability of chromatographic behavior of chiral compounds on different chiral stationary phases which is hypothesized to be of considerable interest for drug development industry, food industry, environmental and agricultural fields as it will reduce the time required for the chiral chromatographic method development.…”