No abstract

No abstract

No abstract

We developed and validated an on-line reverse-phase two-dimensional LC/MS/MS (2D-LC/MS/MS) system for simultaneous determination of the levels of prostaglandin (PG) E(2) as well as PGF(2alpha) and its metabolite 13,14-dihydro-15-keto PGF(2alpha) (F(2alpha)-M) in human plasma. Analytes were extracted by a three-step solid-phase extraction. Samples were then analyzed by on-line 2D-LC/MS/MS with electrospray ionization in negative mode. The 2D-LC system is composed of two reverse-phase analytical columns with a trapping column linking the two analytical columns. While an acidic buffer was used for both separation dimensions, differing organic solvents were employed for each dimension: methanol for the first and acetonitrile for the second to increase resolving power. The 2D-LC/MS/MS method was highly selective and sensitive with a significantly lower limit of quantitation (0.5 pg/mL for PGE(2) and 2.5 pg/mL for PGF(2alpha) and F(2alpha)-M, respectively). Linearity of the 2D-LC/MS/MS system was demonstrated for the calibration ranges of 0.5-50 pg/mL for PGE(2) and 2.5-500 pg/mL for PGF(2alpha) and F(2alpha)-M, respectively. Acceptable precision and accuracy were obtained throughout the calibration curve ranges. This highly selective and sensitive method was successfully utilized to determine the endogenous levels of PGE(2), PGF(2alpha), and F(2alpha)-M in plasma samples from six (four male and two female) normal volunteers. The mean concentrations for each analyte were 0.755 pg/mL for PGE(2), 5.70 pg/mL for PGF(2alpha) and 9.48 pg/mL for F(2alpha)-M.

Landiolol hydrochloride is a newly developed cardioselective, ultra short-acting b 1 -adrenergic receptor blocking agent. Landiolol hydrochloride has much higher cardioselectivity (b 1 /b 2 ϭ255) than currently available b 1 -blockers, such as esmolol hydrochloride (b 1 /b 2 ϭ33).1) This drug is rapidly hydrolyzed by both carboxylesterase in the liver and pseudocholinesterase in the plasma 2) to an inactive metabolite (M-1) with a rapid elimination half-life of about 4 min, which is significantly shorter than the elimination half-lives of conventional b 1 -blockers.3) Based on these features, landiolol hydrochloride has been used in the emergency management of atrial fibrillation, atrial flutter and tachycardia as well as in perioperative arrhythmia control.The introduction of a target controlled infusion (TCI) system into clinical practice ensures that a target plasma drug concentration is obtained to induce and maintain anesthesia during perioperative anesthetic management. Based on a pharmacokinetic model, the TCI system determines the initial loading dose needed to achieve a target plasma drug concentration and the infusion rate needed to maintain a constant concentration, and controls the intravenous infusion completely automatically.4) Therefore, application of the TCI system to landiolol hydrochloride administration is expected to allow more effective and safe drug administration.After the quantitation of landiolol in blood, establishing the pharmacokinetic model is necessary for the application of the TCI system. About the quantitation method of landiolol and its major metabolite, although the summarized method was already reported, 5,6) the method details and validation data had not been reported.In this report, validated HPLC-UV methods that quantitatively determine landiolol and its major metabolite in human blood were reported in order to contribute to progress of clinical research of landiolol hydrochloride such as the application of the TCI system. MATERIALS AND METHODS Chemical and ReagentsLandiolol, M-1, an internal standard for landiolol (IS-1), and an internal standard for M-1 (IS-2) were synthesized at Ono Pharmaceutical Co., Ltd. Methanol, ethanol, acetonitrile, ethyl acetate were HPLC January 2009 121 Notes Validation of HPLC-UV Methods for Quantitatively Determining Landiolol and Its Major Metabolite in Human BloodYoshitaka HASHIMOTO,* Sachiko NAGO, Masako TSUNEKAWA, Kimio SHIBAKAWA, and Yasuyuki MIYATA Pharmacokinetic Research Laboratories, Research Headquarters, Ono Pharmaceutical Co., Ltd.; 17-2 Wadai, Tsukubashi, Ibaraki 300-4247, Japan. Received June 24, 2008; accepted October 15, 2008; published online October 16, 2008 Landiolol is an ultra-short-acting b b 1 -adrenergic receptor blocking agent that is used for both perioperative and postoperative patients with tachycardia during general anesthesia. Validated HPLC-UV methods that quantitatively determine landiolol and its major metabolite (M-1) in human blood were reported for clinical research of landiolol. These analytes were...