Effects of renal insufficiency and hemodialysis on the pharmacokinetics of rofecoxib.

Rofecoxib (VIOXX, Merck & Co., West Point, PA) is a COX-2-selective inhibitor that combines anti-inflammatory and analgesic efficacy with improved gastrointestinal (GI) safety. The present open-label study investigated the pharmacokinetics, safety, and tolerability of a single, oral dose of rofecoxib (50 mg) in patients with end-stage renal failure (creatinine clearance <5 mL/min/1.73 m(2)) requiring hemodialysis. Rofecoxib AUC(0-48 h), AUC(0- infinity), C(max), T(max), and t(1/2) obtained from renal failure patients on hemodialysis were not significantly different from those obtained from healthy subjects. With hemodialysis initiated 48 hours postdose, rofecoxib AUC(0-48 h) adjusted mean ratio (renal failure/healthy subjects) was 0.81, with a corresponding 90% confidence interval (CI; 0.66, 1.00). Hemodialysis per se had no clinically meaningful effect on rofecoxib pharmacokinetics: plasma rofecoxib concentration-time curves were virtually superimposable when hemodialysis was initiated at 4 or 48 hours following rofecoxib dosing, although mean rofecoxib C(max) was 18% lower during the former (325 versus 395 ng/mL; P = 0.014). Overall, rofecoxib was well tolerated in end-stage renal disease patients. In this study, end-stage renal disease and hemodialysis had little effect on rofecoxib pharmacokinetics. Although there are no clinical data to support the use of rofecoxib in patients with severe renal insufficiency (creatinine clearance, 5-30 mL/min/1.73 m(2)), these data suggest that dosage adjustment of rofecoxib is not needed for patients with impaired renal function.

Sensitive method for the quantitative determination of gemfibrozil in dog plasma by liquid-liquid cartridge extraction and liquid chromatography-tandem mass spectrometry.

A sensitive LC-MS/MS assay for the quantitative determination of gemfibrozil in dog plasma has been developed and validated and is described in this work. The assay involved the extraction of the analyte from 0.5-ml aliquots of dog plasma using Chem Elut cartridges and methyl tert.-butyl ether (MTBE). Chromatography was performed on a Metasil Basic column (50 x 2 mm I.D., 3 microm) using a mobile phase that consisted of 70:30 acetonitrile-ammonium acetate (1 mM, pH 5.0) with a flow-rate of 0.2 ml min(-1). The method showed excellent reproducibility with an inter- and intra-assay precision of <8.9% (%RSD), as well as excellent accuracy with an inter- and intra-assay accuracy between 99 and 101%. This method has a lower limit of quantitation (LLOQ) of 1.0 ng ml(-1) with a linear calibration range from 1.0 to 250 ng ml(-1). This new assay offers higher sensitivity and a much shorter run time over earlier methods.

Pharmacokinetics of intramuscularly administered ertapenem.

Ertapenem (INVANZ) is a new once-a-day parental beta-lactam antimicrobial agent that has been shown to be highly effective as a single agent for treatment of various community-acquired and mixed infections. The plasma pharmacokinetics of a 1-g intramuscular (i.m.) dose was compared with those of a 1-g intravenous (i.v.) dose infused over 30 min, the recommended rate of i.v. infusion for comparison, and over 120 min, which more closely mimicked the time course for absorption of the i.m. form. In a three-period crossover study (Part A), 26 healthy subjects received single doses of ertapenem administered i.m., i.v. infused over 30 min, and i.v. infused over 120 min. Blood for ertapenem analysis was collected over 24 h postdose for each treatment. In Part B, these fasted subjects received a 1-g i.m. dose of ertapenem once daily for 7 days. Following a 1-g i.m. dose and a 1-g i.v. dose infused over 120 min, the geometric mean area under the concentration curve from hour 0 to infinity (AUC(0- infinity )) was 541.8 micro g. hr/ml following i.m. administration and 591.4 micro g. hr/ml following a 120-min infusion; the geometric mean ratio was 0.92 with a 90% confidence interval of 0.88 to 0.95. The geometric mean AUC(0- infinity ) was nearly identical when 1-g doses were infused over 30 or 120 min. Although the maximum concentration of drug in serum was somewhat lower following i.m. administration than following i.v. administration, the shape of the plasma concentration profiles was roughly comparable at later time points. Ertapenem did not accumulate after multiple 1-g i.m. daily doses over 7 days. The geometric mean ratio for AUC(0-24) (day 7/day 1) was 0.98 with a 90% confidence interval of 0.94 to 1.02. Thus, the relative bioavailability of the 1-g i.m. dose was 92%. Ertapenem does not accumulate following multiple daily 1-g i.m. doses over 7 days.

Effects of liquid chromatography mobile phase buffer contents on the ionization and fragmentation of analytes in liquid chromatographic/ionspray tandem mass spectrometric determination.

The effects of liquid chromatography mobile phase buffer contents on the ionization and fragmentation of drug molecules in liquid chromatographic/ionspray tandem mass spectrometric (LC/MS/MS) determination were evaluated for simvastatin (SV) and its hydroxy acid (SVA). The objective was to improve further the sensitivity for SV by overcoming the unfavorable condition caused by the formation of multiple major adduct ions and multiple major fragment ions when using ammonium as LC mobile phase buffer. Mobile phases (70:30 acetonitrile-buffer, 2 mM, pH 4.5) with buffers made from ammonium, hydrazine or alkyl (methyl, ethyl, dimethyl or trimethyl)-substituted ammonium acetate were evaluated. Q1 scan and product ion scan spectra were obtained for SV in each of the mobile phases under optimized conditions. The results showed that, with the alkylammonium buffers, the alkylammonium-adducted SV was observed as the only major molecular ion, while the formation of other adduct ions ([M + H](+), [M + Na](+) and [M + K](+)) was successfully suppressed. On the other hand, product ion spectra with a single major fragment ion were not observed for any of the alkylammonium-adducted SVs. The affinity of the alkylammoniums to SV and the basicity of the alkylamines are believed to be factors influencing the formation and abundance of molecular and fragment ions, respectively. Methylammonium acetate provided the most favorable condition among all the buffers evaluated and improved the sensitivity several-fold for SV in LC/MS/MS quantitation compared with that obtained using ammonium acetate buffer. Better precision for SV in both Q1 and SRM scans was observed when using methylammonium buffer compared with those using ammonium buffer. The mobile phase buffer contents did not seem to affect the ionization, fragmentation and chromatography of SVA. The results of this evaluation can be applied to similar situations with other organic molecules in ionspray LC/MS/MS determination.