Pharm 1 - Drug Metabolism - Tomlinson

Front 1

Most metabolism leads to drugs being more polar or nonpolar?

Back 1

Polar - to increase renal drug clearance.

Front 2

Phase 1 metabolism

Back 2

Enzymatic oxidation, reduction or hydrolysis

Principal role is to make inert lipophilic molecules more polar and to put func groups on them to make them reactive substrates for phase II conjugation.

Front 3

Phase 2 metabolism

Back 3

Conjugation of phase 1 metabolites to large, polar molecules (e.g. glucuronic acid) so that metabolites can be readily excreted by the body.

Front 4

Cytochrome P450s

Back 4

Mostly phase I metabolism.

More than 20 families with many subfamilies.

Most of them are expressed in the liver.

Most abundant one is CYP3A4.

Mostly in the ER and it lacks high specificity

Front 5

Specifics about the enzymes of the P450s

Back 5

Heme-containing and membrane bound.

Splits O2 and one O goes to the substrate (the other to water)

Front 6

P450 enzymes need...

Back 6

P450 reductase (to donate electrons), NADPH (the source of electrons), Oxygen, and a lipid bilayer.

Front 7

Mechanisms of P450 induction

Back 7

txpnal, post-txpnal (e.g. mrna turnover), translational, post-translational.

Front 8

Cigarette smoke effect on P450s

Back 8

Induces them

Front 9

General note about inducing P450s

Back 9

Not all are inducible.
Some are inducible only under certain situations.

Front 10

Examples of Phase I reactions

Back 10

Oxidation - epoxidation, hydrooxylation, oxidative N- and O- dealkylation, N-oxidation.

Reduction reactions - Less common.

BUT NOTE - NOT ALL OF PHASE 1 IS DONE WITH P450s! (epoxide hydrolase, spontaneous hydrolysis, oxidation of aliphatic alcohols, hydrolysis)

Front 11

Examples of Phase II reactions

Back 11

Glucuronidation - Most common conjugation rxn for most drugs and xenobiotics. This is done with uridine diphosphate (UDP)-glucuronyltransferase (UDP-GTs)
The level of this enzyme increases until old age. Similar to how the levels of P450s behave.

Beta-glucuronidase

Sulfate conjugation

Glutathione-S-transferases

Methyltransferases

Amino acid conjugation

N-acetylation

Front 12

Neonatal hyperbilirubinemia

Back 12

When newborns lack UDP-GTs at birth so they can't metab bilirubin and thus get CNS damage.

Front 13

Interesting thing about isoniazid metabolism

Back 13

Bimodal distribution of fast metabolizers and slow metabolizers.

Front 14

St. John's Wort - affects on other drugs

Back 14

Induces P450s so it lowers their concentrations.

Front 15

Factors influencing drug metabolism in the elderly

Back 15

Slower/incomplete absorption because less cardiac output.

Changes in drug distribution due to hypoalbuminemia, qualitative changes in drug binding sites, less muscle, more fat, less water.

Less metabolism (livers are worse)

Less excretion (reduced renal blood flow and kidney function)

Less receptors.

BASICALLY, IT APPEARS THAT DRUGS LAST LONGER IN OLD PEOPLE.

Front 16

Grapefruit juice effect on metabolism

Back 16

Inhibits CYP3A4 so drugs stay in you for longer.

Front 17

Charcoal beef does what?

Back 17

Induces P450s

Front 18

Acute alcohol on drugs

Back 18

Inhibits drug metabolism through competitive inhibition

Front 19

Chronic alcohol effects on metabolism

Back 19

Increases drug metabolism and clearance through induction of P450s.

Front 20

ABC (ATP-Binding Cassette) transport proteins

Back 20

P-glycoprotein - Transport parent molecules that are amphiphilic.

MRP - transport phase II conjugates of drugs or their metabolites.