Overcoming Proteasome Inhibitor-Refractory Multiple Myeloma With Elotuzumab, Bortezomib, Nelfinavir, and Dexamethasone.

Multiple myeloma is a common plasma cell malignancy with a median overall survival of fewer than 10 years. Proteasome inhibitors comprise an important part of the treatment regimen for this disease. The present study reports the case of a 57-year-old man who experienced a second relapse of multiple myeloma 6 years after initial treatment with bortezomib, lenalidomide, dexamethasone (VRD) followed by autologous hematopoietic cell transplant.

An improved HPLC assay for the assessment of liver slice metabolic viability using 7-ethoxycoumarin.

The use of precision-cut liver slices constitutes a new in vitro metabolism technique for the study of coupled phase I and phase II biotransformations. This technique has the advantage of being easily amenable to studies with human tissue. As a means of characterizing the metabolic viability of diverse liver samples, a standard substrate capable of undergoing oxidative and conjugative pathways of metabolism would be desirable.

Oxidation of carbovir, a carbocyclic nucleoside, by rat liver cytosolic enzymes. Enantioselectivity and enantiomeric inhibition.

Previous metabolism studies of (-)-cis-carbovir (1'R-cis-2-amino-1,9-dihydro-9-[4'S-hydroxymethyl-2-cyclopenten-1- yl]-6H- purin-6-one), an antiviral agent, have shown that the major route of metabolism of carbovir in the rat is oxidation of the methylene hydroxyl group of the cyclopentadiene ring to form the corresponding 4'-carboxylic acid metabolite. We have determined that rat hepatic alcohol dehydrogenase and aldehyde dehydrogenase are responsible for this biotransformation through sequential oxidation of the alcohol through the aldehyde to the carboxylic acid. The results of incubations of racemic (+/-)-cis-carbovir with rat liver cytosol showed that this oxidation occurs enantioselectively favoring the (+)-enantiomer by a factor of 6- to 7-fold.

The metabolism and excretion of carbovir, a carbocyclic nucleoside, in the rat.

The metabolism and disposition of carbovir [(1R-cis)-2-amino 1,9-(4-(hydroxymethyl)-2-cyclopenten-1-yl)-6H-purin-6-one], an antiviral agent, was examined in rats using an isolated perfused liver, and in vivo following iv and po administration at two dosing levels. HPLC analysis of perfusate and bile after perfusion of the isolated liver with racemic (+/-)[8-3H]carbovir showed conversion to two major metabolites. The major component in the bile was shown to be a glucuronide conjugate of carbovir.