PED2001 Absorption Flashcards
What does ADME stand for?
Absorption, Distribution, Metabolism, Excretion
How do drug molecules primarily move around the body?
Through bulk flow and diffusion
What is bulk flow in the context of drug transport?
Transport through the bloodstream, lymphatics, cerebrospinal fluid, or GI tract
What factors influence diffusion of drug molecules?
Molecular size and lipid solubility
What is the significance of aqueous diffusion?
Crucial for drug transport, especially for large MW drugs
What is the diffusion coefficient dependent on?
1/SQR of molecular weight (MW)
What is the typical molecular weight range for small molecules that can pass through compartments easily?
200-1000 kDa
What are the three ways small molecules cross the cell membrane?
- Diffusing directly through the lipid
- Combination with solute carrier (SLC) or other membrane transporter
- Diffusing through aqueous pores formed by membrane glycoproteins (AQPs)
What is pinocytosis?
The process of invagination of the cell membrane to trap extracellular constituents in a vesicle
True or False: Nonpolar molecules can dissolve freely in membrane lipids.
True
What determines the rate of permeation across a membrane?
Permeability coefficient and concentration difference
What is the partition coefficient?
Expresses solubility for a substance distributed between the membrane phase and aqueous environment
What does diffusivity measure?
Mobility within the lipid, expressed as a diffusion coefficient
What is ‘ion trapping’?
The process where ionisation and membrane permeability affect drug permeation and steady state distribution
What is the Henderson-Hasselbalch equation used for?
To determine the ratio of ionised to unionised forms of weak acids or bases depending on pH
What effect does urinary acidification have on weak bases?
Accelerates excretion
What is the primary role of carrier-mediated transport?
Regulate entry and exit of important molecules across cell membranes
What are ATP-binding cassette (ABC) transporters?
Membrane proteins that couple substrate transport to ATP hydrolysis
What is the role of P-glycoprotein (P-gp)?
To protect the body against xenobiotics and regulate drug transport
What is the main function of BSEP (Bile Salt Export Pump)?
Transport bile salts across the canicular membrane of hepatocytes
What condition is associated with mutations in the ABCC2 gene?
Dublin Johnson syndrome
What are the implications of BCRP (Breast Cancer Resistance Protein) in drug transport?
Secretion of xenobiotics into milk, affecting breast-fed infants
What do SLC transporters primarily do?
Facilitate the transport of a variety of substrates across cell membranes
What types of transporters exist within SLC transporters?
- Facilitative transporters
- Secondary active transporters
What is the role of MRP1 (Multidrug Resistance Associated Protein 1)?
Facilitates extrusion of numerous glutathione, glucuronate, and sulphate conjugates
What is the primary role of MRP2?
Eliminates drug glucuronides in bile
What is the significance of pH partition in drug absorption?
Affects steady-state distribution of weak acids or bases across compartments
What genetic mutation in Collie dogs leads to neurotoxicity from ivermectin?
Lack of MDR1 gene encoding P-glycoprotein
What compound is generated by purine metabolism and can cause effects in joints and kidneys?
Uric acid
High levels of uric acid in synovial fluid can lead to joint issues, while accumulation can cause uric acid kidney stones.
What is the effect of the mutation H155A on proteins?
Makes an unstable protein
How many different gene families do SLC transporters have?
52 different gene families
What are the two types of proteins classified under SLC transporters?
- Facilitative transporters
- Secondary active transporters
What do facilitative transporters do?
Allow substrates to flow downhill with their electrochemical gradients
What do secondary active transporters do?
Allow substrates to flow uphill against their electrochemical gradient by coupling transport to that of a co-substrate
Are secondary active transporters ATP dependent?
No, they are not ATP dependent
What is the OATP family responsible for?
Transporting organic anions across membranes
Which genes encode the OATP family?
SLOC1 to SLOC6 genes
Which OATP proteins are most important for drug disposition?
- OATP1B1
- OATP1B3
- OATP2B1
What type of substrates do OATP1B1 typically transport?
- Statins
- Rifampicin
- Benzylpenicillin
What is the OAT family?
A separate family from OATPs, members of the SLC22A subfamily
Where are OAT1, OAT2, and OAT3 located?
Basolateral membrane of proximal tubule cells, facing blood vessels
What is the role of OAT4?
Located on the apical membrane of proximal tubule, facing urine
What is the substrate coupling mechanism for OAT1 to OAT3?
Coupled to dicarboxylic acid transport
What types of drugs are likely substrates for OAT transporters?
- Sulphated conjugates
- Glucuronide conjugates
Give an example of a substrate for OAT1.
Tetracycline
What are OCTs?
Organic cation transporters
Which OCTs are the most important in human drug disposition?
- OCT1
- OCT2
What types of substrates does OCT1 transport?
- Metformin
- Cisplatin
What is the role of PEPT transporters?
Transport peptides and are involved in drug reabsorption in the kidney
Which family do PEPT transporters belong to?
POT protein family
What types of drugs do PEPT1 and PEPT2 transport?
- Penicillins
- ACE inhibitors
- Valacyclovir
What is the function of MATE transporters?
Export pumps that contribute to biliary and renal excretion of cations
What are the two MATE genes identified?
- MATE1
- MATE2
Where is MATE1 expressed?
In the kidney and liver
Where is MATE2 expressed?
Only in the kidney
What is the role of transporter proteins in the liver and kidney?
Transport xenobiotics into hepatocytes for metabolism and excretion
What is the function of the basolateral membrane in drug transport?
Excretion by tubular secretion or reabsorption into circulation
What happens to compounds at the brush border membrane?
They enter the lumen for final renal excretion
What is the role of CYP2C9 and UGT2B7 in drug metabolism?
Metabolizes diclofenac to acyl glucuronide (DF-AG)
What is the effect of OAT2 and OAT4 on DF-AG?
They excrete DF-AG
What can cause drug-drug interactions involving transporters?
Inhibition of transport in OAT and P-glycoprotein (P-gp)
What is a consequence of OAT inhibition by probenecid?
Slower clearance of penicillin
What is the impact of P-gp on digoxin?
Excretion affected by various drugs, potentially causing toxicity
What does OATP1B1 polymorphism lead to?
Higher plasma levels of some statins due to impaired hepatocyte entry
What condition can arise from OCT2 linked nephrotoxicity?
Fanconi syndrome
What is the proportion of free drug to bound drug when drugs are bound to plasma proteins?
Free drug fraction is less than 1%, bound fraction is 99%
What is the most important protein for drug binding in plasma?
Albumin
What types of drugs does albumin mainly bind?
- Acidic drugs (e.g. warfarin)
- Basic drugs (e.g. TCAs)
What factors influence the amount of drug bound to protein?
- Concentration of free drug
- Affinity for binding sites
- Concentration of protein
What is the significance of fat in drug accumulation?
Acts as a reservoir for non-polar drugs
What can lead to significant drug accumulation in fat?
High administration of benzodiazepines (BZDs)
What is the partition coefficient of morphine?
0.4
Which drug accumulates in bones and teeth and should not be used in children?
Tetracyclines
What can amiodarone lead to during long-term use?
Hepatitis and pulmonary fibrosis
