Materials and methods for determining metabolizer status in humans
The present invention provides methods and materials useful for determining metabolizer status. Embodiments of the present invention provide an approach using a genotyping panel and integration of genotypes of CYP3A4 and CYP3A5 to assess CYP3A metabolizer status, applicable to all CYP3A substrates, including approximately 40% of all drugs. Algorithms for CYP3A metabolizer status are described. Where the contribution ratios of CYP3A4 and CYP3A5 to overall drug levels or drug effects are known, the algorithm can be used to calculate optimal dosing. Where the contributory ratios to overall drug effects are not available, the contributory ratios can be calculated with use of the genotypes for use in drug development. Embodiments of the present invention can be used in optimizing drug treatments, selecting dose, designing therapeutics, and predicting efficacy.
1. A method of administering a dose of a medication to a human in need thereof, comprising: determining the human's metabolizer status genotype for a panel of cytochrome P450 CYP3A alleles according to the following:
i.) extensive metabolizer status if CYP3A4 genotype at rs35599367 is CC and CYP3A5 genotype at rs776746 is AA and CYP3A5 genotype at rs41303343 is a T insertion;
ii.) intermediate metabolizer status if CYP3A4 genotype at rs35599367 is CT and CYP3A5 genotype at rs776746 is AG and CYP3A5 genotype at rs41303343 is a T deletion;
ii.) poor metabolizer status if CYP3A4 genotype at rs35599367 is TT and CYP3A5 genotype at rs776746 is GG and CYP3A5 genotype at rs41303343 is (del T)(del T); administering a dose of medication according to metabolizer status, wherein:
if the human is determined to be an extensive metabolizer, the dose is high,
if the human is determined to be an intermediate metabolizer, the dose is standard, or if the human is determined to be a poor metabolizer, the dose is low;
wherein a high dose is 1.5 to 2.5 times a standard dose, and wherein a low dose is 0.25 to 0.75 of a standard dose.
2. A method of claim 1 , which further comprises communicating the data or risk to at least one human.
3. A method of claim 1 , wherein the at least one genotyping assay is selected from the group consisting of: polymerase chain reaction (PCR), DNA fragment analysis, allele specific oligonucleotide (ASO) probes, DNA sequencing, and nucleic acid hybridization to DNA microarrays or beads, restriction fragment length polymorphism (RFLP), terminal restriction fragment length polymorphism (t-RFLP), amplified fragment length polymorphism (AFLP), and multiplex ligation-dependent probe amplification (MLPA).
4. A method of claim 1 , which further comprises measuring the level of at least one additional liver cytochrome marker in the test sample.
5. A method of claim 1 , wherein said assay is performed using sequencing, 5′ nuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, single-stranded conformation polymorphism, or denaturing gradient gel electrophoresis (DGGE).
6. A method of claim 1 , wherein said nucleic acid is a nucleic acid extract from a biological sample from said human.
7. A method of claim 6 , in which said biological sample is blood, saliva, buccal cells, tissue, plasma, serum, urine, or feces.
8. A method of claim 1 , further comprising providing a report of the identity of the SNP profile.
9. A method of claim 1 further comprising providing a report of said human's increased risk for developing drug overdose or underdose symptoms.