PHAR 813 Test 4 Influence of Pharmacogenomics on Pharmacokinetics and bioavailability II (Drug transport)

Drugs and molecules can cross the membranes by

Simple diffusion, Passive transport (channel or carrier/transport), Active transport (need ATP, against gradient)

Transporter Superfamilies

ABC, SLC

ABC (ATP binding cassette)

Primary active transporters. They need ATP hydrolysis to actively pump substrates across membranes.

SLC (Solute Carrier)

Facilitated transporters and ion-coupled secondary active transporters. OATP, OAT, and MATE

Hepatocyte Influx

OAT1, OAT2, OATP1B1, OATP1B3, OATP2B1

Hepatocyte Efflux

MRP3, MRP4 - MRD1, MATE1, BCRP, MRP2

P-gp

Limits the accumulation of xenobiotics in tissues (efflux). Ex. Limits intestinal absorption, promotes excretion by liver and kidney, and limit tissue accumulation (brain, sperm, fetus)

P-gp substrates

Analgesic, Anticancer agents, HIV and HCV protease inhibitors, Immunosuppressants, Corticosteroids, Antibiotics

Genetic variants: There are at least 1,200 SNPs in the ABCB1 gene.

PGx studies on the role of Pgp (ABCB1)

Inconclusive, No recommendations can be made yet, but think about therapeutic implications on mutations on ABCB1

BCRP (ABCG2)

Contributes to limiting drug accumulation in tissues, expedites hepatobilliary elimination and regulate the different barriers (BBB, placenta, blood-testis)

How many SNP mutations occur with ABCB1?

1,200

How many mutations occur with ABCG2?

35

BSEP (ABCB11)

Bile Salt Export Pump mediates the canalicular step in the transport of bile salts from the systemic circulation into bile.

ABCB11 (BSEP) mutations have been associated with what familial condition? Explain the pathophysiology.

Intrahepatic cholestasis - Reduced expression leads to less efflux of bile salts into bile canaliculus, bile salts accumulate in the liver and circulation and present as cholestasis

OATPB1 (SLC01B1)

Uptake transporters on the basal membrane of hepatocytes

OATPB1 (SLC01B1) Substrates

Bile salts, steroids, hormones, HMG-CoA reductase inhibitors, Antineoplastics, Angiotensin II reductase inhibitors, Antibiotics

Why is important for OATPB1 to be present for statins?

Statins block cholesterol, statin synthesis is in the LIVER so you need the drug in the liver

If hepatic uptake is reduced, what would happen with the hepatic clearance?

Reduced OATP1B1 function will increase drug's AUC values due to reduced hepatic clearance leading to toxicity

OCT1 (SLC22A1)

It is a primary hepatic transporter of cations, METFORMIN is transported by OCT1

What would happen with hepatic metabolism if OCT1 function is reduced?

Reduced

What would happen with drug levels in blood if OCT1 function is reduced?

Increased

What is going to happen with therapeutic efficacy if OCT1 function is reduced and our target is located in the hepatocyte like the case of metformin?

Could decrease

OCT2 (SLC22A2)

It is a primary RENAL transporter of cations. Contributes to the renal secretion of METFORMIN. Contributes to the renal secretion of CISPLATIN Cisplatin causes kidney toxicity

What would happen with renal clearance if OCT2 function is reduced? And what would happen with drug levels in blood?

Renal clearance could be reduced, and drug

levels will be increased

MATE1 (SLC47A1)

It is the apical complement to OCT1 and 2 in hepatocytes and renal cells, pairing the trans-epithelial transport of organic cations.