Sook Wah Yee

Bio: Sook Wah Yee is an academic researcher from University of California, San Francisco. The author has contributed to research in topics: Metformin & Pharmacogenomics. The author has an hindex of 39, co-authored 92 publications receiving 7468 citations. Previous affiliations of Sook Wah Yee include Cardiff University & Georgia Regents University.

Membrane transporters in drug development.

Abstract: Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.

Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing.

Abstract: Thiopurine methyltransferase (TPMT) activity exhibits monogenic co-dominant inheritance, with ethnic differences in the frequency of occurrence of variant alleles. With conventional thiopurine doses, homozygous TPMT-deficient patients (~1 in 178 to 1 in 3,736 individuals with two nonfunctional TPMT alleles) experience severe myelosuppression, 30-60% of individuals who are heterozygotes (~3-14% of the population) show moderate toxicity, and homozygous wild-type individuals (~86-97% of the population) show lower active thioguanine nucleolides and less myelosuppression. We provide dosing recommendations (updates at http://www.pharmgkb.org) for azathioprine, mercaptopurine (MP), and thioguanine based on TPMT genotype.

SLC transporters as therapeutic targets: emerging opportunities

Abstract: Solute carrier (SLC) transporters - a family of more than 300 membrane-bound proteins that facilitate the transport of a wide array of substrates across biological membranes - have important roles in physiological processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics. Several classes of marketed drugs target well-known SLC transporters, such as neurotransmitter transporters, and human genetic studies have provided powerful insight into the roles of more-recently characterized SLC transporters in both rare and common diseases, indicating a wealth of new therapeutic opportunities. This Review summarizes knowledge on the roles of SLC transporters in human disease, describes strategies to target such transporters, and highlights current and investigational drugs that modulate SLC transporters, as well as promising drug targets.

Clinical Pharmacogenetics Implementation Consortium Guidelines for Thiopurine Methyltransferase Genotype and Thiopurine Dosing: 2013 Update

Abstract: The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing was originally published in March 2011. We reviewed recent literature and concluded that although relevant new evidence has been generated, none of the evidence would change the primary dosing recommendations in the original guideline; therefore, the original publication remains clinically current. Up-to-date information on thiopurine methyltransferase (TPMT) gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org). The CPIC of the Pharmacogenomics Research Network (http://www.pgrn.org) and the Pharmacogenomics Knowledge Base (PharmGKB, http://www.pharmgkb.org) provides peer-reviewed, updated, evidence-based, freely accessible guidelines for the translation of genetic laboratory tests into actionable prescribing recommendations for specific drugs.1 CPIC guidelines undergo continuous peer review, and information pertaining to gene-specific alleles and nomenclature is updated periodically on the PharmGKB website. Furthermore, approximately every 2 years, each published guideline and associated Supplementary Data online are reviewed and updated accordingly. The first guideline to be reviewed is the CPIC Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing originally published in March 2011.2 We have done a focused review of the literature between June 2010 and November 2012 on TPMT genotype and thiopurine use (see Supplementary Data, Tables S1–S5, and Figure S1 online). At this time, there is no new evidence that would change our original recommendations in the published guideline; therefore, the original guideline publication remains current. Since the first CPIC guideline was published, the CPIC Steering Committee has recommended that authors address dosing in pediatrics or, at a minimum, comment that there is not enough supporting evidence to allow therapeutic recommendations in pediatrics. As thiopurines are a staple of childhood acute lymphoblastic leukemia and inflammatory bowel disease treatment regimens, much of the evidence (summarized in Supplementary Table S5 online) used to support the original dosing recommendation was generated in children. Furthermore, the dosing recommendations in Table 2 of the main guideline are presented in units of mg/m2 and mg/kg. Therefore, our original guideline dosing recommendations can be used in both the adult and pediatric populations. Although we are not modifying the original main guideline, we have updated the Supplementary Data online to include additional studies that further support our original recommendations (see Supplementary Table S5 online and the Other Considerations subsection of the Supplementary Data online).3,4,5 In addition, we have added information for additional variant alleles not included in the original guideline (see Supplementary Tables S1 and S2 online). Up-to-date information on TPMT gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org).

Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin.

Abstract: ObjectiveThe goal of this study was to determine the effect of a genetic variant in the organic cation transporter 2 (OCT2), OCT2-808G/T, which results in an amino acid change, A270S, on the pharmacokinetics of the antidiabetic drug, metformin.MethodsThe uptake of metformin was performed in stably t

Membrane transporters in drug development.

Abstract: Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.

10 Years of GWAS Discovery: Biology, Function, and Translation

Abstract: Application of the experimental design of genome-wide association studies (GWASs) is now 10 years old (young), and here we review the remarkable range of discoveries it has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics. We predict the likely discoveries in the next 10 years, when GWASs will be based on millions of samples with array data imputed to a large fully sequenced reference panel and on hundreds of thousands of samples with whole-genome sequencing data.