In this work, a high-throughput and high-performance bioanalytical system is described that is capable of extracting and analyzing 1152 plasma samples within 10 hours. A Zymark track robot system interfaced with a Tecan Genesis liquid handler was used for simultaneous solid-phase extraction of four 96-well plates in a fully automated fashion. The extracted plasma samples were injected onto four parallel monolithic columns for separation via a four-injector autosampler. The use of monolithic columns allowed for fast and well-resolved separations at a considerably higher flow rate without generating significant column backpressure. This resulted in a total chromatographic run cycle time of 2 min on each 4.6 x 100 mm column using gradient elution. The effluent from the four columns was directed to a triple quadrupole mass spectrometer equipped with an indexed four-probe electrospray ionization source (Micromass MUX interface). Hence, sample extraction, separation, and detection were all performed in a four-channel parallel format that resulted in an overall throughput of about 30 s per sample from plasma. The performance of this system was evaluated by extracting and by analyzing twelve 96-well plates (1152) of human plasma samples spiked with oxazepam at different concentrations. The relative standard deviation (RSD) of analyte sensitivity (slope of calibration curve) across the four channels and across the 12 plates was 5.2 and 6.8%, respectively. An average extraction recovery of 77.6% with a RSD of 7.7% and an average matrix effect of 0.95 with a RSD of 5.2% were achieved using these generic extraction and separation conditions. The good separation efficiency provided by this system allowed for rapid method development of an assay quantifying the drug candidate and its close structural analog metabolite. The method was cross-validated with a conventional liquid chromatography/tandem mass spectrometry (LC/MS/MS) assay.

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The pharmacokinetics of single doses of cefaclor at 250 and 375 mg and cefuroxime axetil at 250 mg administered under optimal conditions (i.e., cefuroxime axetil after food and cefaclor in the fasted state) were studied in 24 healthy male volunteers. Drug concentrations in serum were related to MICs for common respiratory tract pathogens by using data generated from a recently completed national survey. The time the concentrations in serum exceeded the MICs for Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella (formerly BranhameUla) catarrhalis were significantly greater (P < 0.05) for cefuroxime axetil at 250 mg than for cefaclor at 250 or 375 mg. With the recommended dosing regimens (cefuroxime axetil at 250 mg and cefaclor at 375 mg twice daily or cefaclor at 250 mg three times daily), cefuroxime concentrations exceed the MIC for 90% of the strains tested for a greater time period than cefaclor concentrations with either regimen. The reasons for this difference are (i) the greater potency and slower clearance of cefuroxine compared with those of cefaclor and (ii) the greater sensitivity of these pathogens to cefuroxime.

Alosetron is under clinical development for the treatment of schizophrenia. This study evaluated the effect of oral alosetron dosing on the pharmacokinetics of haloperidol, the latter being administered daily to 13 schizophrenic patients for 56 days. Alosetron 1 mg daily or placebo was given by random assignment for 2 weeks. After a two-week alosetron washout period (during which patients received placebo), patients received the alternate treatment for another two weeks. Serial blood samples were collected for high-performance liquid chromatography determination of plasma haloperidol, reduced haloperidol, and alosetron at selected times for 24 hours after administration of haloperidol and alosetron on study days 21 and 49. Mean pharmacokinetic parameters of haloperidol in the presence of alosetron and placebo treatments were not significantly (P > .05) different: dose-normalized Cmax (6.40 versus 5.75 ng/mL), dose-normalized Cmin (2.00 versus 1.90 ng/mL), dose-normalized AUC (85.97 versus 68.48 ng.hr/mL), and CL/f (78.23 versus 104.7 L/hr). A two-compartment model was used to assess the concentration- and time-independent pharmacokinetics of haloperidol after multiple dosing. The model confirmed that there was no change in the pharmacokinetics of haloperidol when alosetron was administered concomitantly. Mean AUC ratios of reduced haloperidol to haloperidol (0.18) in the presence of alosetron were similar to values obtained in the absence of alosetron, indicating that alosetron had no influence on the metabolism of haloperidol. Mean pharmacokinetic parameters of alosetron were similar to those in previous studies in healthy subjects.

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