The Relative Contributions of CYP3A4 and CYP3A5 to the Metabolism of Vinorelbine

Abstract

Vinorelbine is a semisynthetic vinca alkaloid used in the treatment of advanced breast and non-small cell lung cancers. Vincristine, a related vinca alkaloid, is 9-fold more efficiently metabolized by CYP3A5 than by CYP3A4 in vitro. This study quantified the relative contribution of CYP3A4 and CYP3A5 to the metabolism of vinorelbine in vitro using cDNA-expressed human cytochrome P450s (P450s) and human liver microsomes (HLMs). CYP3A4 and CYP3A5 were identified as the P450s capable of oxidizing vinorelbine using a panel of human enzymes and selective P450 inhibitors in HLMs. For CYP3A4 coexpressed with cytochrome b 5 (CYP3A4+b 5 ) and CYP3A5 +b 5 , the Michaelis-Menten constants for vinorelbine were 2.6 and 3.6 mM, respectively, but the V max of 1.4 pmol/min/pmol was common to both enzymes. In HLMs, the intrinsic clearance of vinorelbine metabolism was highly correlated with CYP3A4 activity, and there was no significant difference in intrinsic clearance between CYP3A5 high and low expressers. When radiolabeled vinorelbine substrate was used, there were clear qualitative differences in metabolite formation fingerprints between CYP3A4+b 5 and CYP3A5+b 5 as determined by NMR and mass spectrometry analysis. One major metabolite (M2), a didehydro-vinorelbine, was present in both recombinant and microsomal systems but was more abundant in CYP3A4+b 5 incubations. We conclude that despite the equivalent efficiency of recombinant CYP3A4 and CYP3A5 in vinorelbine metabolism the polymorphic expression of CYP3A5, as shown by the kinetics with HLMs, may have a minimal effect on systemic clearance of vinorelbine.

Identification of human papillomavirus status specific biomarker in head and neck cancer

“…The HPV status-specific gene sets clearly distinguished the subset of head and neck cancer from normal head and neck, and they included different biological pathways. The HPV1 head and neck cancer-specific gene set consisted of various metabolism-related pathways and this was shown in the previous studies, 20,21 and the HPV-head and neck cancer-specific gene set consisted of collagen degradation, actin-binding, and actin cytoskeleton. 22,23 High activation of STAT1, HPV1 head and neck cancer-specific gene, was associated with negative lymph node status in SCC of the oral cavity and nuclear STAT1 staining in tumor was associated with good prognosis.…”

“…The HPV status‐specific gene sets clearly distinguished the subset of head and neck cancer from normal head and neck, and they included different biological pathways. The HPV+ head and neck cancer‐specific gene set consisted of various metabolism‐related pathways and this was shown in the previous studies, and the HPV– head and neck cancer‐specific gene set consisted of collagen degradation, actin‐binding, and actin cytoskeleton …”

Genetics of antipsychotic drug outcome and implications for the clinician: into the limelight

“…Structurally, CYP3A5 is similar to CYP3A4 but the substrate selectivity of these proteins differ (51, 56Á58). CYP3A5*1 is present in approximately 10Á20% of WhiteEuropean individuals (50) and is present in approximately 55% of African American individuals (51,56,59). Apart from the liver, CYP3A5 is also distributed in the intestine and kidneys (50, 60Á62).…”

Reaction phenotyping of vinblastine metabolism in dogs

“…The CYP3A subfamily of cytochrome P450 enzymes plays an important role in the metabolism of many drugs in humans and may also play a central role in drug metabolism in dogs. Phenotyping of drugs metabolized by the isoforms of such an important subfamily can play a role in the recognition of interactions in combination therapies, recognize auto‐induction or inhibition in multiple dose regimens, and assess the potential impacts of disease on drug metabolism . In addition, polymorphisms of cytochrome P450 enzymes are well studied in humans .…”