Wk5 Introduction To Pharmacokinetics Flashcards
What are pharmacokinetics?
Movement of a drug
Routes of drug administration
Enteral routes ‐ oral, rectal
Parenteral routes
‐ subcutaneous [s.c.], intra‐muscular [i.m.], intra‐venous [i.v.]
Percutaneous ‐ ‘by way of the skin’
‐ inhalation, sublingual, topical/transdermal
What does absorption depend on?
Route of administration
Blood flow at site of administration; surface area
Dose of drug
Active vs passive diffusion through a membrane
Drug solubility
in aqueous body fluids (hydrophilic/lipophobic)
in lipid (hydrophobic/lipophilic)
What does distribution depend on?
Blood flow
brain, heart, liver skeletal muscle fat
Lipid solubility and diffusion barriers ‐ blood brain barrier, placenta
Tissue binding
Plasma protein binding (albumin most common, among several others)
Pharmacokinetic view of the human body
‐ fat (lipophilic) or no fat (hydrophilic)
‐ a lot of membranes…
‐ acidic pH value or not?
‐ active perfusion/pumping or not
‐ large surface area or compact shape
‐ any diffusion barriers?
‐ any inactivating enzymes lurking around?
Apparent volume of distribution (AVD)
The notional volume of fluid required to dilute the absorbed dose to the concentration found in plasma
AVD (volume) = dose [unit of mass] / plasma concentration [mass/volume]
if drug is heavily plasma‐protein bound
AVD ≈ 6 litres
if heavily tissue‐bound
AVD > 70 litres
Passage through layers of cells
Passive diffusion ‐ through cells ‐ involves diffusion through membrane lipids ‐ through intercellular pores ‐ found in some blood vessels ‐ for diffusion of small water‐ soluble molecules
Pinocytosis – facilitated diffusion and active transport ‐ of limited importance for drugs
Lipid solubility and “ion trapping”
Many drugs exist in an equilibrium between ionised and unionised forms
Only the unionised form is sufficiently lipid‐soluble to diffuse through membranes
Many drugs are “weak” acids or “weak” bases
‐ meaning their pKa values are in the physiological pH range ‐ the degree of ionisation depends on local pH
Drugs will tend to accumulate in areas where ionisation is favoured
Properties of ionisable groups can be described by the Henderson‐Hasselbalch equation
Henderson-Hasselbalch equation
PH = pKa + log10([A-]/[HA])
pKa value is a quantitative expression of the strength of an acid or a base. Acetic acid has a pKa of 4.76 CH3‐COOH => CH3‐COO‐ + H+
This means, at pH = 4.76 there are same amounts of free acid and acetate ion.
Lipid solubility and “ion trapping” acidity
Ion trapping does not require any enzyme or energy. It is similar to osmosis
in that they both involve the semi‐permeable nature of the cell membrane.
Thus, weak acids will tend to be well absorbed from acid environments and accumulate in basic environments. Weak bases will tend to be well absorbed from basic (alkaline) environments and accumulate in acidic environments.
Ion trapping is the reason why basic (alkaline) drugs are secreted into the stomach (for example morphine), where pH is acidic,
and acidic drugs are excreted in urine when it is alkaline.
but NB the influence of
‐ bulk flow
‐ absorptive surface
Metabolism
Usually inactivates drug, but not always “prodrugs” – e.g. L‐DOPA
paraceptamol => toxic metabolites
Diazepam => active metabolite desmethyldiazepam (oxidative demethylation by a number of CYPs)
Tamoxifen => active metabolite 4‐hydroxy‐tamoxifen (oxidation by CYP2D6 and CYP3A4)
First pass metabolism – different biotransformations
Phase I Oxidation via cytochrome p450 enzymes Phase II Conjugation reactions Phase I = introduction of hydroxyl groups Phase II = charged groups are conjugated (linked) to compounds = compounds get even more hydrophilic Groups to be linked: sulfate, glucuronidate and others
“Phase I” and “phase II” are historical names for these reactions. In the liver, they occur simultaneously.
Excretion
Kidney ‐ into urine Liver ‐ into bile ‐ enterohepatic circulation
Lungs
also into saliva, sweat, milk
Urine and saliva are routinely used for drug analytics (in addition to blood)
PRE‐CLINICAL OUTCOMES FROM DOING a pharmacokinetics study
- Select compounds that have the maximum potential of reaching the target (PK)
- Select the appropriate route of administration to deliver the drug
- Understand how the blood (or plasma) levels relate to efficacy (PK‐PD) or toxicity (TK‐TD) in order to select safe doses
- Decide on the frequency and duration of dosing in order to sustain drug at target for disease modification
- Predict Human pharmacokinetics (gender?)
PERFORMING A PK STUDY
Dose
COLLECT SAMPLES (BLOOD, URINE, BILE, FECES) AT VARIOUS TIMEPOINTS
ANALYZE FOR DRUG/METABOLITES PK DATA ANALYSIS
