Thomas F. Woolf

IDENTIFICATION OF A POTENTIALLY NEUROTOXIC PYRIDINIUM METABOLITE OF HALOPERIDOL IN RATS

In vivo metabolic studies have revealed that haloperidol is converted to the corresponding pyridinium metabolite which has been characterized in both urine and brain tissues isolated from haloperidol treated rats. Unlike the corresponding conversion of the structurally related Parkinsonian inducing agent MPTP to the ultimate neurotoxic pyridinium metabolite MPP+, the oxidative biotransformation of haloperidol is not catalyzed by MAO-B. Microdialysis studies in the rat indicate that intrastriatal administration of this pyridinium metabolite is about 10% as effective as MPP+ in causing the irreversible depletion of striatal nerve terminal dopamine. The results point to the possibility that some of the neurological disorders observed in experimental animals and man during the course of chronic haloperidol treatment may be mediated by this pyridinium metabolite.

Biotransformation of ketamine, (Z)-6-hydroxyketamine, and (E)-6-hydroxyketamine by rat, rabbit, and human liver microsomal preparations.

1. (Z)- and (E)-6-Hydroxyketamine have been synthesized and their metabolism by hepatic microsomal preparations studied to elucidate the metabolism of ketamine. 2. Both 6-hydroxyketamines are exclusively converted to 6-hydroxy-norketamines by N-demethylation. The g.l.c. retention properties and mass spectral characteristics of these 6-hydroxy-norketamines were used to confirm the structures of ketamine metabolites. 3. Ketamine is converted to norketamine, 4-, 5- and 6-hydroxynorketamines and possibly 4- and 6-hydroxyketamines in hepatic microsomal preparations from rats, rabbits and man. Norketamine is the major metabolite in all species tested. 4. 6-Hydroxynorketamine is the major hydroxylated metabolite and is found only in the (Z)-form in the species examined. 5. The metabolism of ketamine and the 6-hydroxy-ketamines is greatly increased after phenobarbital pretreatment of rats and rabbits.

Inhibition of MDR3 Activity in Human Hepatocytes by Drugs Associated with Liver Injury

MDR3 dysfunction is associated with liver diseases. We report here a novel MDR3 activity assay involving in situ biosynthesis in primary hepatocytes of deuterium (d9)-labeled PC and LC-MS/MS determination of transported extracellular PC-d9. Several drugs associated with DILI such as chlorpromazine, imipramine, itraconazole, haloperidol, ketoconazole, sequinavir, clotrimazole, ritonavir, and troglitazone inhibit MDR3 activity. MDR3 inhibition may play an important role in drug-induced cholestasis and vanishing bile duct syndrome. Several lines of evidence demonstrate that the reported assay is physiologically relevant and can be used to assess the potential of chemical entities and their metabolites to modulate MDR3 activity and/or PC biosynthesis in hepatocytes.