Study discovers why leading gout medication is ineffective for many

Study discovers why leading gout medication is ineffective for many

Allopurinol, the first-choice medication for treating gout—an excruciatingly painful condition that is the most common form of inflammatory arthritis, afflicts more than eight million Americans, and is on the rise worldwide—is not fully effective in more than half of patients.

A recent study led by UCSF School of Pharmacy researchers identified a key genetic difference determining patient response to allopurinol. In addition, their lab work showed how that difference results in reduced drug efficacy by altering the activity of a specific drug transporter, a type of protein molecule that spans cell walls and controls the entry and exit of drugs.

This allopurinol study is the first to look at genetic differences between patients who respond differently to the drug (pharmacogenomics). It could ultimately yield tests to indicate in advance which gout patients will not respond well to allopurinol and instead may need newer, more expensive medications that are less frequently prescribed but would be more effective for them.

The study, published in the May issue of Clinical Pharmacy and Therapeutics, was senior-authored by School faculty member Kathy Giacomini, PhD, and lead-authored by Christopher Wen, a graduate student in her lab. The Giacomini Lab, which focuses on the role of membrane transporters in drug disposition and response, is based in the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine.

Journal citation: Wen CC, Yee SW, Hoffmann TJ, Kvale MN, Banda Y, Jorgenson E, Schaefer C, Risch N, Giacomini KM, “Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response,” Clinical Pharmacy and Therapeutics, May 2015, Vol. 5, p. 518-25.

The challenge

Gout is caused by hyperuricemia—an abnormally high level of uric acid in the blood. Uric acid is created when the body breaks down purines, which are found in foods and in the body’s own tissues. Normally, excess uric acid is excreted, primarily by the kidneys. When this fails to occur due to factors such as genetics, diet, medications, and/or kidney disease, uric acid crystals form and accumulate in the joints (notably the base of the big toe), producing episodes of swelling and pain lasting days or weeks.

Gout in X-ray of left foot; the base of the big toe is commonly affected.

While gout flare-ups are treated with anti-inflammatory drugs, allopurinol prevents the disease episodes by combating the hyperuricemia that leads to them—reducing levels of blood serum uric acid (SUA) to six milligrams per deciliter or less, when effective. But it is estimated that only 42 percent of patients on allopurinol achieve that therapeutic goal.


It was long thought that allopurinol worked solely by inhibiting the enzyme that converts purines into uric acid. But more recent studies by Giacomini’s lab and others have found that the drug also inhibits the URAT1 transporter protein that provides for reabsorption of uric acid into the body in the renal tubules—the part of the kidney that sorts out what substances in the blood the body will retain and which it will excrete in urine.

The research

To search for genetic differences in allopurinol response, the researchers used genomic data from more than 2,000 Northern California patients in the Kaiser Permanente medical care plan who were prescribed the drug. The patients were among the more than 110,000 Kaiser plan members—dubbed the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort—who provided their DNA and gave broad consent for use of their data and health records for research into the causes and treatment of common diseases by scientists at Kaiser Permanente and UCSF.

Giacomini and colleagues performed a genome-wide association study, sequencing the DNA of each study subject and comparing them for variations, including differences in individual building blocks (single nucleotide polymorphisms or SNPs) among the approximately 3.2 billion that comprise an individual human’s genome.

That data was compared to patients’ uric acid reduction from allopurinol, as drawn from electronic pharmacy records and test results.

The results

The researchers found a key difference in a gene (ABCG2) that affected drug response.

The ABCG2 gene encodes a transporter protein called BCRP that is known to be involved in uric acid outflow (efflux) from cells and ultimately excretion from the body via the kidneys, “but [BCRP] has not previously been associated with allopurinol transport or response,” write Giacomini et al.

More precisely, they found a variant of the ABCG2 gene with a single nucleotide difference (SNP) that, in turn, changes a single amino acid in the encoded transporter, which reduces the protein’s functionality and is associated with reduced efficacy of the drug.

To further confirm that the BCRP protein is an allopurinol transporter and to understand how this particular SNP affects drug response, the researchers performed experiments combining the drug, labeled by radioactive isotopes for tracking, with cells expressing normal BCRP proteins, no BCRP, and the variant form found in patients with reduced drug response.

They found that, indeed, the BCRP transporter pumps allopurinol out of cells, but the variant form is significantly less effective at doing so, leading to lower accumulation of the drug in the urine. Therefore, in patients with the BCRP variant, less of the drug would be available to inhibit uric acid reabsorption via the URAT1 transporter; thus, more uric acid would be reabsorbed into the body, leading to higher SUA and a less effective treatment.
 


About the School: The UCSF School of Pharmacy is a premier graduate-level academic organization dedicated to improving health through precise therapeutics. It succeeds through innovative research, by educating PharmD health professional and PhD science students, and by caring for the therapeutics needs of patients while exploring innovative new models of patient care. The School was founded in 1872 as the first pharmacy school in the American West. It is an integral part of UC San Francisco, a leading university dedicated to promoting health worldwide.