The Effects of BCRP Q141K on Allopurinol Pharmacokinetics and Dynamics

Phase 4

Completed

Brief Summary: Subjects will undergo a placebo and allopurinol phase to better understand the effects of the reduced function BCRP Q141K variant on allopurinol pharmacokinetics and pharmacodynamics.

Recruitment & Eligibility

Inclusion Criteria

self-identified as Asian/European ancestry
generally healthy with approved lab values for CBC,HFP,RFP, and uric acid
Subjects with the ABCG2 genotype, homozygous, heterozygous or homozygous for the major allele of rs2231142 will be recruited

Exclusion Criteria

vascular disease
renal impairment
medications/supplements that affect uric acid levels
pregnant or lactating women
prior history of allergic reaction to allopurinol or testing positive for HLA-B*5801 allele
risk of urinary or gastric retention or narrow-angle glaucoma
impaired hepatic function
evidence of anemia
evidence or diagnosis of congestive heart failure
smokers
subjects with a mutation other than rs2231142 in the ABCG2 genotype
subjects taking hormonal contraceptives or other hormonal medications
evidence of recreational drug use as determined by questionnaire

Arm && Interventions

Group	Intervention	Description
BCRP Q141K CC	Placebo	Participants that are homozygous reference for BCRP Q141K receive at least one 300 mg dose of allopurinol followed by blood/urine collection for up to 72 hours post-dose.
BCRP Q141K AA	Placebo	Participants homozygous for the BCRP Q141K allele receive at least one 300 mg dose of allopurinol with blood/urine collection for up to 72 hours post-dose.
BCRP Q141K CA	Placebo	Participants that are heterozygous for the BCRP Q141K allele receive at least one 300 mg dose of allopurinol, with blood/urine collections up to 72 hours post-dose.
BCRP Q141K CC	Allopurinol	Participants that are homozygous reference for BCRP Q141K receive at least one 300 mg dose of allopurinol followed by blood/urine collection for up to 72 hours post-dose.
BCRP Q141K CA	Allopurinol	Participants that are heterozygous for the BCRP Q141K allele receive at least one 300 mg dose of allopurinol, with blood/urine collections up to 72 hours post-dose.
BCRP Q141K AA	Allopurinol	Participants homozygous for the BCRP Q141K allele receive at least one 300 mg dose of allopurinol with blood/urine collection for up to 72 hours post-dose.

Primary Outcome Measures

Name	Time	Method
Percent Change Uric Acid	24 hours	Maximum percent change in uric acid after a single dose of allopurinol
Oxypurinol Renal Clearance	24 hours (Urine collected 0-4 hrs,4-8 hrs,8-10 hrs,10-24 hrs post-dose)	Renal clearance as defined by amount excreted in 24 hours/AUC from 0-24 hours

Secondary Outcome Measures

Name	Time	Method
Oxypurinol AUC	24 hours (Collections at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24 hours post-dose)	Area under the concentration time curve from 0-24 hours following a single dose of allopurinol (i.e. Day 1 of both protocols)