Lecture 5 - Pharmacokinetics Flashcards
What does pharmacokinetics provide?
an understanding of the FATE of the dose of a drug administered, the time course and levels of the unbound drug in the body
What does drug effects depend on?
- Pharmacodynamics: mechanism of action and effects on cellular functions (receptors, ion channels, enzymes, transporters)
- Physicochemical properties of the drug (affinity, efficacy and potency)
What does the physicochemical properties of the drug affect in pharmacokinetics?
ADME (concentration):
- Absorption
- Distribution
- Metabolism
- Excretion
Describe the process of drug distribution and absorption through the body
- Bulk flow transfer through the blood stream (CV system)
- Diffusion
Movement of drugs between compartments usually involves penetration of lipid diffusion barriers (i.e. cell membranes) which determines where and for how ling a drug will be present in the body after administration
The drug is required to cross the plasma membrane. Many small molecules can travel across via diffusion or by dissolving. The speed of this is based on the molecular weight - e.g. larger = slower.
Pinocytosis (fluid endocytosis)
Once across the membrane and in bulk flow, the physical/chemical properties are less important
What are factors affecting absorption - diffusion through lipids?
Physiochemical properties of drug
- Lipid solubility partition coefficent ((high partition coefficient = easily enters plasma membrane)
- Diffusivity
Non-polar (uncharged) molecules dissolve freely in lipids and penetrate cell membranes freely
- higher rate of absorption from gut
- higher penetration into brain and other tissues
- higher renal elimination
What is one of the most important determinants of the pharmacokinetics characteristics of a drug?
Lipid solubility - polar molecules are less effective at crossing membranes
What are other factors affecting absorption?
- pH and ionization
- Many drugs are weak acids or bases
e.g. weak acid HA <–> H+ + A- - leaving a charged acid, which means it won’t cross membranes easily
- putting the drug in an acidic environment leads to the acid being more likely to be non-dissociated (uncharged) - cross membranes more easily
- weak acid donates protons
What is the Henderson-Hasselbach equation?
pKa = pH + log10(HA/A-)
At low pH weak acids will be un-ionized.
Only uncharged species can cross lipid.
Describe how pH affects steady-state distribution of drugs between aqueous compartments
Basic environment (i.e. pH > 7) favours dissociation of acids. Weak acids become ‘trapped’ in basic compartment e.g. renal tubules. Urinary acidification retards excretion of weak acids. Increasing plasma pH (e.g. sodium bicarbonate) causes weakly acidic drugs to be extracted from CNS into plasma where they get ‘trapped’. Reduction in neurotoxicity - e.g. following poisoning with aspirin.
What are factors involved in the route of administration influencing drug absorption?
- Orally
- Pre/cutaneous absorption
- Intravenous delivery
- Intramuscular delivery
- Intrathecal (cerebrospinal fluid- e.g. epidural)
- Inhalation
What is bioavailability?
The fraction of ingested dose that gains access to circulation
What are factors affecting absorption? (transport)
- Carrier mediated transport - passive or active solute carrier (SLC) transports.
- ATP-binding cassette (ABC) transporters - e.g. sugars, amino acids, metal ions, neurotransmitters.
- Drugs compete with normal substrate
- over 300 human genes are believed to code these transporters, most of which act mainly on endogenous substrates, but some also transport foreign chemicals including drugs.
- Absorption (and elimination) of such drugs will be affected by saturation and competitive inhibition at the transporter
- Drug transporters usually have extensive binding affinity toward a broad spectrum of small molecule substrates and inhibitors - implication for drug-drug interactions and pharmacokinetics
How are genetic variants of organic cation transporter 1 (OCT1) associated with different responses to metformin in healthy humans?
In the presence of Metformin (diabetes drug), glucose regulation was less effective in patients carrying a polymorphism that impaired OCT1 function.
Type 2 diabetes - high levels of glucose due to non-functional insulin receptors
Metformin works at the liver in glucose handling. The Metformin doesn’t work in people with this gene, which codes for a transporter.
What are the 4 main fluid compartments of the body in which a drug distributes?
- Plasma
- Intracellular water
- Interstitial water
- Transcellular water
(non-water compartment - fat)
What compartment will a non-polar drug want to travel?
Fat - if not it will be distributed between the 4 compartments
