Boris A. Czeskis

Absolute bioavailability of evacetrapib in healthy subjects determined by simultaneous administration of oral evacetrapib and intravenous [13C8]-evacetrapib as a tracer

This open‐label, single‐period study in healthy subjects estimated evacetrapib absolute bioavailability following simultaneous administration of a 130‐mg evacetrapib oral dose and 4‐h intravenous (IV) infusion of 175 µg [13C8]‐evacetrapib as a tracer. Plasma samples collected through 168 h were analyzed for evacetrapib and [13C8]‐evacetrapib using high‐performance liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameter estimates following oral and IV doses, including area under the concentration‐time curve (AUC) from zero to infinity (AUC[0‐∞]) and to the last measureable concentration (AUC[0‐tlast]), were calculated. Bioavailability was calculated as the ratio of least‐squares geometric mean of dose‐normalized AUC (oral : IV) and corresponding 90% confidence interval (CI). Bioavailability of evacetrapib was 44.8% (90% CI: 42.2–47.6%) for AUC(0‐∞) and 44.3% (90% CI: 41.8–46.9%) for AUC(0‐tlast). Evacetrapib was well tolerated with no reports of clinically significant safety assessment findings. This is among the first studies to estimate absolute bioavailability using simultaneous administration of an unlabeled oral dose with a 13C‐labeled IV microdose tracer at about 1/1000th the oral dose, with measurement in the pg/mL range. This approach is beneficial for poorly soluble drugs, does not require additional toxicology studies, does not change oral dose pharmacokinetics, and ultimately gives researchers another tool to evaluate absolute bioavailability.

Synthesis of multidrug resistance modulator LY335979 labeled with deuterium and tritium

Dideutero and ditritioisotopomers of the multidrug resistance modulator LY335979 were prepared by initial bromination of 5-hydroxyquinoline under acidic conditions followed by Mitsunobu coupling of 6,8-dibromo-5-hydroxyquinoline with (S)-glycidol. Opening of the resulting epoxide with dibenzosuberylpiperazine LY335995 resulted in dibromoanalog of LY335979, which was finally reductively debrominated with deuterium or tritium in the presence of palladium on carbon.

Synthesis of(S)-1-(1H-indol-4-yloxy)-3-[4-(3-methoxyphenyl)-4-hydroxypiperidin-1-yl)-propan-2-ol (LY333068) succinate, and its 3-[14C]-isotopomer based on chiral glycerol-[14C] derivatives

The 3-[14C]-isotopomer of (S)-1-(1H-indol-4-yloxy)-3-[4-(3-methyoxyphenyl)-4-hydroxypiperidin-1-yl]-propan-2-ol (LY333068), a 5HT1A antagonist, was prepared in 10 steps and 8.2% radiochemical yield from (L)-serine-[3-14C]. Deamination, esterification, and protection of the resulting diol gave methyl (R)-2,2-dimenthyl-1,3-dioxolane-4-carboxylate-[3-14C], as a chiral and radiolabeled building block, which then was subsequently coupled with 4-hydroxyindole and 4-(3-methoxyphenyl)-4-hydroxypiperidine to give the titled product with 99.4% radiochemical purity.

Identification, synthesis and pharmacological activity of moxonidine metabolites

The metabolism of moxonidine, 4-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-6-methoxy-2-methyl-5-pyrimidinamine, LY326869, in rats, mice, dogs, and humans has been examined. At least 17 metabolites were identified or tentatively identified in the different species by HPLC, LC/MS and LC/MS/MS. The identities of seven of the major metabolites have been verified by independent synthesis. The metabolites are generally derived from oxidation and conjugation pathways. Oxidation occurred at the imidazolidine ring as well as the methyl at the 2 position of the pyrimidine ring. All seven metabolites were examined in the spontaneously hypertensive rats (3 mg kg(-1), i.v.) for pressure and heart rate. Only one, 2-hydroxymethyl-4-chloro-5-(imidazolidin-2-ylidenimino)-6-methoxypyrimidine, exerted a short-lasting decrease in blood pressure, albeit attenuated in magnitude compared to moxonidine.