Phenotype:UGT1A1 intermediate metabolizer

A UGT1A1 intermediate metabolizer (IM) is a person whose UGT1A1 alleles together produce reduced, but not substantially absent, enzyme activity. It is one of the three metabolizer phenotypes assigned from UGT1A1 genotype, sitting between the poor metabolizer and the normal metabolizer. UGT1A1 has no rapid or ultrarapid phenotype. This page describes the intermediate-metabolizer phenotype; the enzyme itself is covered at Enzyme:UGT1A1.

The intermediate metabolizer is a milder version of the poor metabolizer: the toxic irinotecan metabolite SN-38 is cleared somewhat slowly, and atazanavir produces somewhat more hyperbilirubinemia, but in each case to a lesser degree than in the poor metabolizer.

Genotype basis

The intermediate-metabolizer phenotype is produced by a UGT1A1 diplotype that pairs one normal-function allele with one reduced-function allele, most often \*1/\*28, \*1/\*6, or \*1/\*37. The full allele catalogue is described on the Enzyme:UGT1A1 page.

Population frequency

The UGT1A1 intermediate-metabolizer phenotype is common, found in roughly 35 to 45% of European-ancestry populations and at comparable frequencies elsewhere, varying with the local prevalence of the reduced-function alleles. It is, in most populations, the single most common UGT1A1 phenotype, because carrying exactly one reduced-function allele is more probable than carrying two or none.

Clinical consequences

Irinotecan (clearance; modestly raised exposure of the toxic metabolite). A UGT1A1 intermediate metabolizer clears the active irinotecan metabolite SN-38 somewhat more slowly than a normal metabolizer, with an intermediate risk of severe neutropenia and diarrhea. The Dutch Pharmacogenetics Working Group guideline addresses the genotype-to-phenotype spectrum for irinotecan; its most definite dose-reduction recommendation is for the \*28/\*28 poor-metabolizer genotype, while heterozygous intermediate metabolizers carry a smaller and dose-dependent excess risk.

Atazanavir (hyperbilirubinemia). An intermediate metabolizer given the UGT1A1-inhibiting protease inhibitor atazanavir develops hyperbilirubinemia of intermediate degree, less marked than in a poor metabolizer but more than in a normal metabolizer.

Bilirubin. A single reduced-function allele produces, at most, a slight elevation of unconjugated bilirubin, often within the normal reference range. The full biochemical picture of Gilbert syndrome is associated with the poor-metabolizer phenotype rather than the intermediate one.

See also

• Enzyme:UGT1A1, the enzyme, its history, and its full substrate spectrum.
• Phenotype:UGT1A1 poor metabolizer, Phenotype:UGT1A1 normal metabolizer, the sibling phenotypes.
• Irinotecan, Atazanavir (representative affected medicines).
• Category:Pharmacogenomic phenotypes