Documente Academic
Documente Profesional
Documente Cultură
Metabolic Pathways and
Transporters
PROFESSIONAL DOCUMENTATION
Drug metabolism
Drugs are metabolized by two types of reactions. PHASE I reactions include oxidation, reduction and hydrolysis, while
PHASE II reactions involve conjugation, among others. The cytochrome P450 family of enzymes is responsible for most
oxidation reactions (phase I), and glucuronidation (phase II) is mediated through a family of enzymes called UDP
glucuronosyltransferases.
Nomenclature
Cytochromes and UDPglucuronosyltransferases are enzyme superfamilies. In the literature, each superfamily is identified by
an abbreviation, namely CYP for cytochrome P450 and UGT for UDPglucuronosyltransferase. Superfamilies are further
divided into families and subfamilies. Each isoenzyme is therefore identified by a number indicating the family, a letter
indicating the subfamily, and another number denoting the specific isoform.
CYP 3 A 4
UGT 2 B 7
Metabolism via the cytochrome P450
Cytochromes are highly expressed in the liver and intestine. The following isoenzymes are in large part responsible for the
metabolism of drugs: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4. CYP3A4 alone is involved in the
biotransformation of 50 to 60% of all drugs. Interindividual differences, due mainly to the genetic polymorphism that exists in
certain CYP subfamilies, have a significant influence on drug metabolism. This genetic variation may cause differences in a
person's ability to metabolize drugs. CYP2D6 is one of the best known polymorphic enzymes. For example, some individuals
are described as "poor metabolizers" (5 to 10% of Caucasians) when they have two nonfunctional CYP2D6 alleles.
Cytochromes and drug interactions
Certain drugs can inhibit or induce CYP enzymes, resulting in an increase or decrease, respectively, of serum concentrations
of the substrates involved.
Inhibition of the CYP
Several mechanisms can contribute to the inhibition of the CYP enzymes responsible for the metabolism of a substrate:
Competitive reversible inhibition: the most common. The inhibitor and the substrate compete to bind to the active site
of the enzyme.
Noncompetitive reversible inhibition: the inhibitor does not prevent the substrate from binding to the active site of the
enzyme. In fact, the inhibitor binds to the enzyme but not to the active site, which causes the structure of the enzyme to
change and become inactive.
Reversible inhibition occurs rapidly (varies between a few hours to 23 days).
Irreversible inhibition: longer lasting than reversible inhibition because enzymes must be resynthesized before
activity is restored.
http://isp:7005/hw_vigilance_monograph/docproform/en/docpro22.htm?&back 1/3
3/16/2019 Metabolic Pathways and Transporters
Induction of the CYP
The presence of certain substrates stimulates the cells to produce more enzymes, which increases metabolic efficiency.
Induction is gradual and is dependent on the inducer, dose and duration of treatment. Induction may develop after several
days or weeks and can last just as long after treatment completion.
Metabolism via UGTs
UGTs are mainly expressed in the liver, but are also present to a lesser extent in the kidneys, intestine, and lungs. Expression
of these enzymes is subject to genetic polymorphism. UGTs are responsible for glucuronidation reactions. These reactions
generally abolish the pharmacologic activity of drugs. Additionally, certain substances can inhibit or induce these enzymes.
UGTs are increasingly being used to explain a certain number of drugdrug interactions.
Membrane transporters
After a drug is dissolved, it crosses the intestinal barrier (enterocytes) and is transported to the liver (hepatocytes) via the
portal vein before entering the systemic circulation from where it is distributed to the body's various tissues. Then, the drug is
either eliminated by hepatic metabolism (primarily) or excreted in the urine or bile. During these pharmacokinetic processes,
transporters allow drug substances to enter or exit through the biological membranes. Transporters are located in the
intestine, biliary tract and renal proximal tubule, among others.
Transporters are divided into two superfamilies:
ABC (ATPbinding cassette)
SLC (solutelinked carrier)
ABC transporters are responsible for removing substances from cells (efflux), while SLC transporters are generally involved in
the uptake.
BCRP breast cancer resistance protein
BSEP bile salt export pump
The role of the transporters varies depending on the tissue in which the transporter is expressed. Here are the roles played by
the key drug transporters:
Intestinal transporters
In the intestine, Pgp, MRP2 and BCRP limit the oral bioavailability of drugs (efflux).
OATP transporters facilitate the absorption of drugs (uptake).
Hepatic transporters
http://isp:7005/hw_vigilance_monograph/docproform/en/docpro22.htm?&back 2/3
3/16/2019 Metabolic Pathways and Transporters
OATP1B1, OATP1B3, OATP2B1 and OCT1 transporters are responsible for the uptake of drugs from the blood into
hepatocytes. The drug is then eliminated by hepatic metabolism or biliary excretion.
Pgp, BCRP, MRP2 and BSEP are involved in the elimination of drugs by biliary excretion (from hepatocytes to bile)
(efflux).
Renal transporters
OCT2, OAT3 and OAT1 transporters carry drugs from the blood into the renal proximal tubule (uptake).
Pgp, MRP2, MATE1, MATE2K and BCRP take drugs from the renal proximal tubule to urine (efflux).
The transporters can be inhibited or induced by certain substrates. The table below presents the impact on the area under the
curve (AUC) as a result of the inhibition of several transporters involved in drug transport.
Impact of inhibiting the transporter on the drug's
Family Transporter Direction
AUC
Genetic polymorphism may, as is the case with certain cytochromes, cause changes in transporter activity.
Vigilance Santé | © All rights reserved
http://isp:7005/hw_vigilance_monograph/docproform/en/docpro22.htm?&back 3/3