Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

110 Applying Pharmacogenomics in Therapeutics
allele showed threefold higher plasma levels of diflomotecan, an anticancer drug,
with an intravenous administration of the drug. In addition to chemotherapeutic
drugs, BCRP also plays an important role in the disposition of rosuvastatin, a member
of the statin class drugs used to treat high cholesterol and related conditions. The
BCRP C421A polymorphism influences the pharmacokinetics and therapeutic effect
of rosuvastatin in Chinese and white populations.
Organic Anion–Transporting Polypeptides
Organic anion–transporting polypeptide (OATP) is a family of membrane proteins
mediating the transport of mainly organic anions across the cell membrane. There
are currently 11 members of this family, encoded by genes that are classified as the
Solute Carrier Organic Anion (SLCO) gene subfamily. OATPs are expressed in various
organs, such as the liver, intestine, and kidneys. OATPs have a wide variety of
substrates, including endogenous substrates such as bile acids, bilirubin, and numerous
hormones including thyroid and steroid hormones, and a diverse range of drug
compounds such as antibiotics, lipid-lowering drugs, antidiabetic drugs, and various
anticancer drugs, including pazopanib, vandetanib, nilotinib, canertinib, and erlotinib
(Khurana et al. 2014).
The major members of the OATP family include OATP1B1, OATP1B3, and
OATP2B1. They show overlapping but some different expression patterns. OATP1B1,
OATP1B3, and OATP2B1 are expressed in the liver on the basolateral membrane
of hepatocytes to facilitate uptake of their substrates from the portal circulation.
OATP1B1 and OATP1B3 are expressed exclusively in the liver but OATP2B1 expression
is more ubiquitous. Genetic variations in these OATPs contribute to the interindividual
differences in drug response.
OAT1B1 is a liver-specific transporter protein encoded by the SLCO1B1 gene
(solute carrier organic anion transporter family, member 1B1) located at chromosome
12p12. This transporter is formerly known as organic anion transporter 2
(OATP2), OATPC, liver-specific transporter 1 (LST1), and SLC21A6. OATP1B1 is
responsible for mediating active transport of many endogenous substrates such as
bile acids, xenobiotics, and a broad range of pharmaceutical compounds including
antidiabetic drugs and chemotherapeutic agents. The SLCO1B1 gene is highly polymorphic,
with 190 common variants identified. By designation, the SLCO1B1*1a
represents the wild-type allele. There are two well-characterized common nonsynonymous
alleles: rs2306283 (SLCO1B1: 492A>G on NM_006446.4, previously
referred to as 388A>G; encoding OATP1B1: N130D) and rs4149056 (SLCO1B1
625T>C on NM_006446.4; commonly referred to as T521C, encoding OATP1B1:
V174A). Due to partial linkage disequilibrium, there are four important haplotypes
with these two variants: SLCO1B1*1A containing neither variant, SLCO1B1*1B
(rs2306283), SLCO1B1*5 (rs4149056), and SLCO1B1*15 with both variants. In
addition to variants in the coding region, there is also a promoter variant, termed
g.-11187G>A, which is found in conjunction with SLCO1B1*1B (N130D) and
SLCO1B1*5 (V174A). The haplotype containing this promoter variant g.-11187G>A
in combination with these two common nonsynonymous variants is designated as
SLCO1B1*17.