SLIDE 1
Pharmacokinetics
- Absorption
- Distribution
- Metabolism
- Excretion
Pharmacokinetics, tissue distribution, cellular accumulation and - - PowerPoint PPT Presentation
Pharmacokinetics, tissue distribution, cellular accumulation and - - PowerPoint PPT Presentation
Pharmacokinetics, tissue distribution, cellular accumulation and relation to activity Kimmo Malminiemi National Agency for Medicines Finland Basics of ADME; definitions, formulae Steady-state situation Classical receptor occupancy theory
SLIDE 2
SLIDE 3
Plasma concentration after oral administration
CP time
Lag time Tmax Distribution phase Elimination phase Cmax T½ elim Oral dose Cmax = observed peak concentration Tmax = time to peak T½ elim= apparent half-life
- f elimination
AUC = area under the plasma concentra- tion - time curve Absorption phase
SLIDE 4
Volume of distribution
Vdist= amount of drug in body / concentration
F * Dose
Vappr=
kelim * AUC Clear * T½elim = 0.693
F = bioavailability kelim = elimination time constant = 0.693 / T½ elim
SLIDE 5
Steady-state concentration in plasma
- modified from Goodman & Gilman’s The Pharmacological Basis of Therapeutics
SLIDE 6
Concentration in plasma, formulae
F * Dose
CSS = Clear * Dint
F * Dosing rate
= Clear F = bioavailability Dint = dosage interval
Peak:
F * Dose / VSS Cmax= 1 - frac
Trough:
Cmin = frac * Cmax
Where
VSS = volume of distribution at steady state frac = fraction of the last dose in the body at the end of a dosing interval frac = 1 - exp (- 0.693 * Dint / T½ elim )
SLIDE 7
Accumulation in tissues
- pH gradient; generally, only unionized form penetrates
lipid membranes
- binding to intracellular constituents
- partitioning into lipid phase
Consequences
- reservoir : retarded release
- prolonged action, compared to T½ elim from plasma
Factors affecting accumulation
SLIDE 8
Classical receptor occupancy theory
k1
Drug + Rec k2 DrugRec
Stimulus Response
eff
Response = Fnc
[Drug] [Drug] + k2/k1
x [Rec] x eff
( )
EC50= concentration needed for half-maximal effect Efficacy: L> M Potency: L> N Signal amplification
SLIDE 9
Receptor - stimulus - response, examples
Receptor binding effect organ effect
Beta-2 AR GS, adenyl cyclase vasodilation Alpha-1 AR GI, phospholipases vasoconstriction NM cholinerg Na+ -channel depolarization 5-HT2A phospholipase C platelet aggregation Estrogen ERα DNAERE activation mRNA synthesis AT1-R PLA, Janus kinase gene transcription Insulin receptor tyrosine kinase… …cell growth Dihydrofolate inhibition of inhibition of reductase the enzyme DNA synthesis 50 S ribosomal translocation of inhibition of unit tRNA protein synthesis bacteriostatic effect
SLIDE 10
Receptor binding
Order of affinity to receptor: A > B > C
SLIDE 11
Inefficient coupling of receptor occupancy
SLIDE 12
Moderate coupling of receptor occupancy
SLIDE 13