Mosely- Drug Disposition

Question 1

Xenobiotic

Answer 1

any chemical that is considered foreign to a biological system (ex: a drug in a pt.); can be natural compound if it is not expected to be present, but usually refers to drugs, pollutants, or other toxic compounds.

Question 2

Drug

Answer 2

Any substance that brings about change in biologic function through its chemical actions; used in the treatment, cure, prevention or diagnosis of disease.

Question 3

Prodrug

Answer 3

in inactive form of a drug that in converted to an active form in the body.

Question 4

Drug disposition

Answer 4

Qualitative description of how the body handles the drug; includes how the drug is absorbed, where dist., how metabolized, and how it is eliminated (ADME).

Question 5

Pharmokinetics (PK)

Answer 5

Quantitative description of drug disposition

Question 6

Pharmacodynamics (PD)

Answer 6

The actions of the drug on the body; usually mediated through drug actions on specific cellular receptor proteins.

Question 7

LADME

Answer 7

Liberation: Release of drug from formulation
Absorption: Transport of drugs from site of administration into general circulation.
Distribution: Delivery of drug via blood to different tissues of the body.
Metabolism: Conversion of parental compound to metabolites.
Excretion: Removal of compounds and metabolites.

Question 8

Passive Transfer: Filtration (Bulk Flow)

Answer 8

Passage of drugs through membrane pores. Restricted by molecular size (<300-500 Daltons). Important for getting drugs into circulation and in tissues (except CNS). Also important in glomerular filtration.

Question 9

Passive Transfer: Passive Diffusion

Answer 9

Directly through membrane by dissolving in and diffusing across it. Important because most enteral route uses this method. Properties: Must be uncharged (Non_Ionized) and Lipid Soluble.

Question 10

Acidic Drug

Answer 10

Neutral molecule that can reversibly dissociate into an anion (Neg. charged molecule)(Conjugate Base) to yield a proton.

Question 11

Basic Drug

Answer 11

Neutral molecule which can form a cation (positively charged) (conjugate acid) by combining with a proton.

Question 12

Carrier Mediated Transport

Answer 12

1. Carrier Proteins- Broad substrate specificity, saturable.
2. Facilitated Diffusion- Transports down chemical or concentration gradient. Energy independent. Saturable. Bi-Vectorial. SoLute Carrier (SLC).
3. Active Transport- Against concentration gradient. Saturable. Energy Dependent. Primary= Self contained energy machinery. Secondary=ATP is provided by another source other than the transporter.

Question 13

ABC Transporter Superfamily

Answer 13

ATP Binding Cassette Transporter Family.

• Primary active transporters; 7 families (A-G) with 48 isoforms.
• Mediate Vectorial (Unidirectional) transport across a monolayer of polarized cells such as endothelial or epithelial.
• 3 Isoforms: MDR proteins, MRP, and BCRP.

Question 14

MDR Proteins

Answer 14

Multi-Drug Resistance proteins.

• MDR1 (ABCB1) aka P-glycoprotein.
• Efflux transporter selective for organic cations and neutral molecules with bulky structures. Pumps anticancer drugs out of neoplastic cell.

Question 15

MRP

Answer 15

Multidrug Resistance Protein- MRP2 (ABCC2)
- Efflux transporter selective for organic anions- glucuronide, sulfate and GSH conjugated metabolites of drugs. Similar tissue/cellular distribution as MDR1.

Question 16

BCRP

Answer 16

Breast Cancer Resistant Protein (ABCG2)

-Neutral and negatively charged molecules- doxorubicin

Question 17

SLC Transporter Superfamily

Answer 17

SoLute Carrier

• 2 types: Facilitated diffusion transporters and 2ndary active transporters.
• Bidirectional
• OAT, OCT, Neurotransmitter reuptake transporters

Question 18

OAT

Answer 18

Organic Anion Transporter (OAT1) (SLC22A6)

• Transports organic anions. Ex: diuretics, NSAIDS, antiviral/antibiotics, ACE inhibitors, etc.
• Primarily expressed on basolateral (blood) side of membrane of renal proximal tubular cells; uptake anionic drugs into these cells in exchange for endogenous dicarboxylates.

Question 19

OCT

Answer 19

Organic Cation Transporter- OCT2 (SLC22A2).

-Transports organic cations. Ex: antihistamines, metformin, nicotine, etc.

Question 20

Neurotransmitter Reuptake Transporters

Answer 20

Transports excess NTs from synapse to presynaptic nerve.

i) DAT (dopamine transporter, SLC6A3)
ii) SERT (Serotonin transporter, SLC5A4)

Question 21

Receptor-Mediated Endocytosis

Answer 21

• Drug binds specific membrane receptors
• Drug-receptor complex engulfed by cell membrane.
• Membrane pinches off to form drug filled vesicle
• Vesicle is transported into cell
• Active transportation modality- requires energy for rearrangement of cell membrane to engulf drug-receptor.
• Limited to transport of large polypeptides and proteins across cell membrane.

Question 22

Different Drug Transfer processes

Answer 22

1) Filtration- Not energy dependent, not saturable, selects on size.
2) Passive diffusion: Not energy dependent, not saturable, selects on lipophilic/charged.
3) Facilitated diffusion: Not energy dependent, Saturable, Is selective.
4) Active transport: Energy dependent, saturable, selective.