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Pomaglumetad methionil (LY2140023) is the prodrug of a novel metabotropic glutamate 2/3 receptor agonist (LY404039) being investigated for the treatment of schizophrenia. Using accelerator mass spectrometry (AMS) and an intravenous (i.v.) radiolabeled tracer approach, the absolute bioavailability of the prodrug and the extent of its conversion to active moiety (LY404039) were estimated at presystemic (intestinal/first pass) and systemic sites after simultaneous oral and i.v. dosing in healthy subjects. The mean absolute bioavailability of prodrug (80 mg oral) was 0.68. On the basis of these data and a previous radiolabeled mass balance study in which no prodrug was recovered in feces, we concluded that 0.32 of the dose is converted to active drug in the intestinal tract. The fraction of prodrug converted to active moiety was approximately 1, indicating complete conversion of the prodrug that reaches the systemic circulation to the active moiety. Prodrug (80 mg oral and 100 μg i.v.) and active moiety (100 μg i.v.) were well tolerated in healthy subjects. Thus, the absolute bioavailability of prodrug LY2140023 and the fraction converted presystemically and systemically to active moiety LY404039 were estimated simultaneously using radiolabeled tracer microdosing and AMS., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

A sensitive bioanalytical method for the measurement of two major circulating metabolites of duloxetine [4-hydroxy duloxetine glucuronide (LY550408) and 5-hydroxy-6-methoxy duloxetine sulfate (LY581920)] in plasma is reported. This method produced acceptable precision and accuracy over the validation range of 1-1000 ng/mL. Several issues had to be addressed in order to develop an LC/MS/MS assay for these metabolites. First, 4-hydroxy duloxetine glucuronide required chromatographic resolution from the 5-, and 6-hydroxy duloxetine glucuronide isomers. Second, the glucuronide conjugate is readily ionized under positive ESI conditions, while the sulfate conjugate required negative ESI conditions to obtain adequate sensitivity. Finally, the chromatographic conditions needed to separate the glucuronide isomers were not suitable for the analysis of the sulfate conjugate. The present method addressed these challenges, and was successfully applied to multiple human pharmacokinetic studies in which subjects received oral doses of duloxetine hydrochloride.

A reversed-phase high-performance liquid chromatographic method was developed to quantify a decapeptide anticoagulant in rat and monkey plasma. The compound and internal standard, a nonapeptide analogue, were extracted from plasma with an amino solid-phase extraction column with an extraction efficiency in the range 75-90%. A C18 analytical column was used to separate the analytes by gradient elution followed by ultraviolet detection at 215 nm. Quantification of the decapeptide over the concentration range 0.1-10.1 micrograms/ml resulted in an assay relative error and relative standard deviation both less than 10%. The anticoagulant decapeptide was stable in both rat and monkey plasma frozen at -20 degrees C.

The concentrations of the (R)- and (S)-enantiomers of fenoprofen (alpha-methyl-3-phenoxy-benzeneacetic acid) were measured in plasma and urine of volunteers after oral administration of the (R,S)-racemate. In addition, urinary concentrations of the (R)- and (S)-4'-hydroxy metabolite of fenoprofen, the major metabolite, were measured. The (R)-enantiomer of fenoprofen was stereoselectively inverted to (S)-fenoprofen, which was the major isomeric form found in plasma and urine. A potency comparison of the enantiomers in vitro showed the (S)-isomer to be 35 times more active than the (R)-isomer in inhibiting the fatty acid cyclo-oxygenase pathway from human platelets. In vivo, the similar pharmacological potency of the two enantiomers previously observed in experimental animals may have been due to the rapid inversion of the (R)- to (S)-isomer.

Reversed-phase high-performance liquid chromatographic methods have been developed to quantitate the R- and S-enantiomers of flurbiprofen and its major metabolites, 4'-hydroxyflurbiprofen, 3'-hydroxy-4'-methoxyflurbiprofen, and 3',4'-dihydroxyflurbiprofen. The compounds are extracted from plasma or urine and derivatized with S-(alpha)-methylbenzylamine to form diastereomeric amides which are readily separated on a C18 column. Fluorescence detection resulted in detection limits that readily allowed us to characterize the disposition of R- and S-flurbiprofen and its major metabolites in man following therapeutic doses.