Isobaric product ions cannot be differentiated by exact mass determinations, although in some cases deuterium labeling can provide useful structural information for identifying isobaric ions. Proposed fragmentation pathways of fentanyl were investigated by electrospray ionization ion trap mass spectrometry coupled with deuterium labeling experiments and spectra of regiospecific deuterium labeled analogs. The major product ion of fentanyl under tandem mass spectrometry (MS/MS) conditions (m/z 188) was accounted for by a neutral loss of N-phenylpropanamide. 1-(2-Phenylethyl)-1,2,3,6-tetrahydropyridine (1) was proposed as the structure of the product ion. However, further fragmentation (MS(3)) of the fentanyl m/z 188 ion gave product ions that were different from the product ion in the MS/MS fragmentation of synthesized 1, suggesting that the m/z 188 product ion from fentanyl includes an isobaric structure different from the structure of 1. MS/MS fragmentation of fentanyl in deuterium oxide moved one of the isobars to 1 Da higher mass, and left the other isobar unchanged in mass. Multistage mass spectral data from deuterium-labeled proposed isobaric structures provided support for two fragmentation pathways. The results illustrate the utility of multistage mass spectrometry and deuterium labeling in structural assignment of isobaric product ions.

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Death occurred in sheep following diethylamine oxyquinoline sulphonate (DOS) copper injections given at recommended dose rates. The copper content in unused portions of DOS copper packs was normal and free of bacterial contamination. Liver and blood copper levels in dead and sick sheep were not high. Sick sheep showed signs of hepatic encephalopathy and dead sheep were generally piled against fences and scrub. Deaths were associated with acute, severe, generalised, centrilobular, hepatocellular necrosis and live sheep had elevated circulating levels of liver enzymes consistent with liver damage. In recovered sheep there were no residual complications. It would appear that even at 0.5 mg/kg of DOS copper the safety threshold may sometimes be exceeded in some sheep.

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Purpose This study was conducted to evaluate potential pharmacokinetic interactions between docetaxel and atrasentan as part of a phase I/II clinical trial. Methods Patients with prostate cancer were treated with intravenous docetaxel (60-75 mg/m2) every three weeks and oral atrasentan (10 mg) daily starting on day 3 of cycle 1 and then given continuously. The pharmacokinetics of both drugs were evaluated individually (cycle 1, day 1 for docetaxel; day 21 for atrasentan) and in combination (cycle 2 day 1 for both drugs). Pharmacogenomics of alpha-1-acid glycoprotein (AAG) were also explored. Results Paired pharmacokinetic data sets for both drugs were evaluable in 21 patients. Atrasentan was rapidly absorbed and plasma concentrations varied over a 4 fold range at steady-state within a typical patient. The median apparent oral clearance of atrasentan was 17.4 L/h in cycle 1 and was not affected by docetaxel administration (p = 0.9). Median systemic clearance of docetaxel was 51.1 L/h on the first cycle and significantly slower (p = 0.01) compared to that obtained with co-administration of atrasentan, 61.6 L/h. Docetaxel systemic clearance in cycle 1 was 70.0 L/h in patients homozygous for a variant allele in AAG compared to 44.5 L/hr in those with at least one wild type allele (p = 0.03). Conclusion Genetic polymorphism in alpha-1-acid glycoprotein may explain some inter-patient variability in docetaxel pharmacokinetics. The systemic clearance of docetaxel is increased by approximately 21 percent when given concomitantly with atrasentan, however atransentan pharmacokinetics do not appear to be influenced by docetaxel administration.