Pharmacokinetics Flashcards
What is Lipinski’s Rule of Five?
Orally active drugs generally show a balance of hydrophilic / hydrophobic properties and obey at least three of the following rules:
- MW < 500
- No more than 5 HBD groups
- No more than 10 HBA groups
- log P < +5
What is the relationship between oral bioavailability and number of freely rotatable bonds and flexibility
of the molecule?
- The more flexible the molecule, the less likely it is to be orally active.
- To measure flexibility, count the # of freely rotatable bonds that result in significantly different conformations
How are polar drugs absorbed?
- Poorly absorbed, usually administered by injection.
- Some highly polar drugs are absorbed from the digestive system by ‘hijack’ transport proteins present in the membranes of cells lining the gut wall
What is the partition coefficient?
The relative distribution of a drug between an aqueous and non-aqueous phase
P = Concentration of drug in octanol/
Concentration of drug in aqueous solution
Hydrophobic compounds have a high P value
Hydrophilic compounds have a low P value
Please comment on drug distribution as mentioned in class
- Once across the gut wall, the drug enters blood vessels
- Cells lining the blood vessels are loose fitting
- Drug can quickly cross blood vessel walls through pores between the cells
- Drugs absorbed orally are first taken to the liver
- Modification of the drug is possible by enzymes in the liver; drug metabolism
- A certain percentage of the absorbed drug is often deactivated by drug metabolism in the liver before distribution occurs round the body; first pass effect
- Blood concentration drops rapidly after absorption due to distribution, macromolecular binding, and storage in fat tissue or bone (e.g. barbiturates stored in fat tissue)
- Blood brain barrier hinders polar drugs from entering brain
- tight fitting cells line the capillaries in the brain
- capillaries have a coating of fat cells
Drug is distributed evenly throughout the blood supply within 1 min of absorption
What is the first pass effect?
A percentage of orally absorbed drug is metabolised in the liver prior to distribution round the body
What are Phase I and Phase II reactions?
Metabolic reactions are defined as phase I or phase II
- Most phase I reactions add a polar ‘handle’ to the molecule
- Oxidations (catalysed by cytochrome P450 enzymes)
- Phase II reactions are often carried out on functional groups which have been added by Phase I reactions
- Most phase II reactions are conjugation reactions catalysed by transferase enzymes.
- Increasing the polarity of a compound increases the rate of drug excretion (see drug excretion)
Why is it hard to estimate a safe dosage for barbiturates
Becuase they are fat soluble.
What is the effect of the blood-brain barrier on drug absorption?
- Cell membranes and caplilaries are coated in fatty cells
- Thus, polar drugs do NOT enter the brain easily
- Can design drugs with no CNS effects
Why is phenobarbital contraindicated with warfarin?
Phenobarbital enhances activity of P450 enzymes
and accelerates the metabolism of warfarin, making it less
effective
Why are some drugs contraindicated with antibiotics?
- Several antibiotics can act as cytochrome P450 inhibitors and will slow the metabolism of drugs metabolized by these enzymes
How do Brussel sprouts, grapefruit and cigarette smoking affect drug metabolism?
- Brussel sprouts & cigarette smoke enhance activity of cytochrome P450
- Grapefruit juice inhibits activity of cytochrome P450
Why is fexofenadine (Allegra) administered as an anti-histamine, instead of the prodrug terfenadine
If metabolism is inhibited by grapefruit juice, terfenadine persists in the body and can cause serious cardiac toxicity. As a result, fexofenadine is now favored over terfenadine.
Terfenadine is a prodrug and is metabolized to the active agent fexofenadine.
Why is it that more polar the drug, the easier it is for it to be excreted?
Due to a concentration gradient, hydrophobic compounds are efficiently reabsorbed back into the blood, whereas polar compounds remain in the nephron and are excreted
