A novel method has been developed for the rapid solid phase extraction of drugs and metabolites from biological fluids, prior to further analysis. The newly designed, 96-tube micropreparation block facilitates high throughput by enabling the extraction of 96 samples simultaneously. The system is described, linked to HPLC/APCI-MS/MS, for the determination of darifenacin in human plasma. The resulting procedure, using deuterated darifenacin as internal standard, is validated over the concentration range 25-2000 pg/mliter; accuracy (0.6-4.6%) and precision (3.6-18.8%) are considered acceptable and overall recovery was determined to be approximately 50%.

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1. UK-240,455 ((+) 6,7-dichloro-5-[N-(2-hydroxyethyl)methanesulphonamido]-2,3 (1H,4H)-quinoxalinedione) is a potent, selective N-methyl D-aspartate (NMDA) glycine site antagonist that is being evaluated for the potential treatment of stroke. 2. UK-240,455 is predominately excreted unchanged in urine (58-68%) in rats, dogs and man following intravenous administration. The remainder of the dose is excreted unchanged in the faeces. It is considered that UK-240,455 is predominantly cleared by active renal tubular secretion and active hepatobiliary transport. In man, there is evidence that UK-240,455 undergoes glucuronidation. However, there is no evidence for this in rats and dogs. 3. UK-240,455 has a short elimination half-life in rats, dogs and man (0.4-1.4 h) and clearances of 12, 13 and 6 ml min(-1) kg(-1), respectively. The compound shows limited tissue distribution with volumes of distribution of 0.4-0.8 l kg(-1) in rats, dogs and man. The species' variation in pharmacokinetic parameters was related allometrically when plasma protein binding was taken in to account. Hence, active hepatic or renal clearance processes for this compound were conserved across species. 4. Cerebrospinal fluid and brain concentrations of UK-240,455 were determined in rats. The cerebrospinal fluid/plasma concentration ratio of UK-240,455 was 4.3%, which was similar to the plasma-free fraction of this compound (3%), indicating good blood-brain barrier permeability. Brain tissue concentrations were low (0.7% of the total plasma concentrations).