Potential impact of cytochrome P450 3A5 in human liver on drug interactions with triazoles.

Article Details

Citation

Yamazaki H, Nakamoto M, Shimizu M, Murayama N, Niwa T

Potential impact of cytochrome P450 3A5 in human liver on drug interactions with triazoles.

Br J Clin Pharmacol. 2010 Jun;69(6):593-7. doi: 10.1111/j.1365-2125.2010.03656.x.

PubMed ID
20565450 [ View in PubMed
]
Abstract

Cytochrome P450 3A is the main enzyme subfamily involved in the metabolism of a variety of marketed medicines. It is generally believed that the substrate specificity of polymorphic P450 3A5 is similar to that of the predominant P450 3A4 isoform, although some differences in catalytic properties have been found. It has been hypothesized that individuals with CYP3A5 1 (P450 3A5 expresser) might clear the HIV protease inhibitor saquinavir, administered by mouth, more rapidly than subjects lacking functional CYP3A5 alleles. Enhanced midazolam hydroxylation and cyclosporin metabolism occur in an in vitro P450 3A5 system and in liver microsomes expressing P450 3A5 in the presence of thalidomide. However, inhibition constants (K(i)) of three triazole anti-fungal drugs (itraconazole, fluconazole, and voriconazole) for liver microsomal P450 3A5 are higher than for liver microsomal P450 3A4. To predict drug interactions in vivo, we estimated increases of areas under the curves (AUC) dependent on polymorphic P450 3A5 expression, using both 1 +[Inhibitor] / K(i) (recommended in US FDA guidance), and 1 +[Inhibitor](unbound) / K(i) (as recommended by Japanese MHLW Notice). Voriconazole would be expected to cause approximately a three-fold higher increase in AUC in subjects with CYP3A5 3/3 than in those with CYP3A5 1/3, especially when estimated using the FDA guidance. We conclude that drug interactions between marketed drugs may differ substantially between individuals with genetically distinct P450 3A5 catalytic functions.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
VoriconazoleCytochrome P450 3A5ProteinHumans
Unknown
Substrate
Inhibitor
Details
Drug Interactions
DrugsInteraction
Alfentanil
Mibefradil
The metabolism of Alfentanil can be decreased when combined with Mibefradil.
Alfentanil
Troglitazone
The metabolism of Alfentanil can be decreased when combined with Troglitazone.
Alfentanil
Chloramphenicol
The metabolism of Alfentanil can be decreased when combined with Chloramphenicol.
Alfentanil
Imatinib
The metabolism of Alfentanil can be decreased when combined with Imatinib.
Alfentanil
Gestodene
The metabolism of Alfentanil can be decreased when combined with Gestodene.