Thalidomide metabolism and hydrolysis: mechanisms and implications.

Despite its controversial past, thalidomide is currently under investigation for the treatment of several disease types, ranging from inflammatory conditions to cancer. The mechanism of action of thalidomide is complex and not yet fully understood, but there is some evidence to suggest that metabolism may play a role. Consequently, there has been a considerable effort to characterize the metabolism of thalidomide in recent years.

Synthesis of racemic cis-5-hydroxy-3-phthalimidoglutarimide. A metabolite of thalidomide isolated from human plasma.

[reaction: see text] A synthesis of the glutarimide-derived metabolite of thalidomide, 5'-hydroxythalidomide (2), is described. The synthesis employed the lactone derivative of N-benzyloxycarbonyl (CBZ)-protected 4-hydroxyglutamic acid 12, which is prepared by a de novo route from diethyl acetamidomalonate. The reaction of 12 with 4-methoxybenzylamine gave the corresponding isoglutamine, which then provided the key CBZ-protected N-PMB-glutarimide 14 after dehydration.

Effect of common CYP3A4 and CYP3A5 variants on the pharmacokinetics of the cytochrome P450 3A phenotyping probe midazolam in cancer patients.

Purpose: To evaluate the effect of naturally occurring variants in genes encoding the cytochrome P450 (CYP) isoforms CYP3A4 and CYP3A5 in patients with cancer receiving midazolam as a phenotyping probe.

Experimental Design: Five variants in CYP3A4 and CYP3A5 were evaluated in 58 patients (21 women and 37 men) receiving a short i.v.

Mechanisms of resistance to anticancer drugs: the role of the polymorphic ABC transporters ABCB1 and ABCG2.

ATP-binding cassette (ABC) genes play a role in the resistance of malignant cells to anticancer agents. The ABC gene products, including ABCB1 (P-glycoprotein) and ABCG2 (breast cancer-resistance protein [BCRP], mitoxantrone-resistance protein [MXR], or ABC transporter in placenta [ABCP]), are also known to influence oral absorption and disposition of a wide variety of drugs. As a result, the expression levels of these proteins in humans have important consequences for an individual's susceptibility to certain drug-induced side effects, interactions, and treatment efficacy.