pharmacokinetics Flashcards
routes of administration
§ Intravenous - rapid response
§ Intramuscular
§ Subcutaneous
§ Oral - slowest response
Cmax
maximum concentration
Tmax
time taken to reach maximum concentration
MEC
minimum effective concentration
MTC
minimum toxic concentration, above which drug toxicity occurs
ability to cross lipid membranes depends on
size, solubility, polarity/charge, transporters
size affecting ability to cross lipid membranes
® Oral absorption decreases with increasing molecular weight
◊ Drugs that are too big may be poorly absorbed from the GI tract
lipinki’s rule
drug should be <500 g/mol
□ Solubility
affecting drugs ability to cross lipid membranes
® Orally absorbed drugs need a mix of 2 physiochemical properties
◊ Hydrophilicity (water loving)
◊ Lipophilicity (fat loving)
2 means of estimating lipid solubility
logP and polar surface area (PSA)
logP
} Layer of organic fluid (octanol) over water, add drug, mix, allow layers to equilibrate
} Measure ratio of drug concentrations both phases (partition coefficient) [P]
– Log of partition coefficient [LogP] predicts ability of drugs to cross membranes
◊ Polar surface area (PSA)
computer based PSA prediction based on amount of surface of the molecule that has a polar surface
◊ Egan’s egg
} Most drugs in clinical use lie in an egg shape in a graph of PSA against logP
□ Polarity/charge
◊ Drugs only diffuse across lipid membranes if they are in a neutral (uncharged) state
□ Transporter
® Drug transporters can influence drug accumulation and efflux
® P-glycoprotein
◊ P-Gp is a clinically-significant membrane transporter
◊ Member of ATP-binding cassette-type membrane transporters
p glycoprotein is encoded by
ABCB1 gene
what does p glycoprotein do
◊ Can return absorbed drug to gut lumen
} P-gp is an efflux pump (ATP dependant) that counteracts the oral absorption of lipophilic drugs
drug bioavailability is reported as
F ie. Fraction of administered dose that is absorbed
prodrugs
® Hydrophilic groups in molecule can be masked by adding metabolism-sensitive, lipophilic substituents
® After entering cell, group is cleaved, releasing the drug
transported affecting drug distribution
§ Key roles ABC transporters and SLC transporters
plasma concentrations of blood
§ Lipid soluble drugs distribute into fat and can achieve low plasma concentrations
§ Highly protein bound drugs distribute poorly into tissues and yeild higher plasma concentrations
Vdist
dose/plasma concentration(Co)
Co
® C naught value is estimated plasma concentration at time = 0
acidic drugs mainly stored by
albumin
basic drugs mainly stored by
binds an a1 glycoprotein
major drug transformations in the human body
oxidation, sulfonation, glucuronidation, glutathione conjugation, acetylation, etc
2 phases of metabolism
oxidative reactions
conjugative reactions
oxidative reactions are
functionalisation reactions
○ Introduce or expose a new functional group
Conjugative reactions involve
formation of a new chemical bond between drug and an endogenous molecule (donated by a cofactor)
○ Ie. Formation of a conjugate
oxidative reactions examples
○ Oxygenation, hydroxylation, N-Dealkylation
conjugative reactions examples
○ Sulfonation, acetylation, gluceronidation, methylation, glutathione conjugation
DMEs
drug metabolising enzymes
cytochrome P450
CYP
§ Iron-containing proteins (contain Fe in haem group)
§ High versatile oxidising systems (many substrates)
cofactors for CYP
§ Require NADPH (cofactor) & oxygen (O2) to metabolise drug substrate (SH)
4 CYP families in humans
□ CYP1 □ CYP2 □ CYP3 □ CYP4 □ 1-3 most important in human drug metabolism □ 4 metabolises fatty acids
metabolism or renal clearance more important?
Metabolism is more important than renal clearance or bile
2 CYP related properties of drugs that influencee clinical use of pharmaceuticals
CYP inducers and
CYP inhibitors
induction of CYP450
◊ CYP expression can be increased by drugs and chemicals
induction occurs via
◊ Usually occurs via drug receptors
} Xenosensors
} Bifunctional transcription factors
– After release from cytosol, act as tfs at CYP gene promoters
– Increased transcription o f CYP gene
– Increased CYP enzyme
- CYP inhibitors (inhibition)
- Common DDI mechanism (drug-drug interactions)
2 main types of CYP inhibition
competitive and mechanism based
◊ Competitive inhibition
} Occurs if 2 drugs compete for the same CYP isoform
} One drug inhibits the metabolism of the other
Mechanism based inhibitors
} Drug forms a chemically reactive metabolite
} Attacks active site of CYP
Grapefruit juice
◊ Contains furanocoumarin compounds which competitively inhibit gut CYP3A4 (not liver)
◊ Impair drug transport/excretion
◊ Affects drug with low oral availability
2 examples of conjugative reactions
glucuronidation
sulfonation
○ Glucuronidation
§ Very common reactions
§ Adds glucuronic acid (sugar) to a drug
sulfonation
§ Forms sulfonate on a OH or NH2 group of drug
□ Enzyme is sulfotransferase
type of drugs kidneys excrete
Excretes relatively small, water-soluble drugs and their metabolites into urine
○ Three processess control levels of drugs and their metabolites in urine
glomerular filtration
passive diffusion
active transport
- Glomerular filtration
- Free (unbound) drugs in blood are filtered through pored in glomerulus (pass into ultrafiltrate)
- Passive diffusion
- Some drugs can passively diffuse back into blood (occurs for lipophillic and nonionised drugs)
- Active transport
- Energy-dependant transporters move drugs from blood into urine (at the proximal tubules)
renal clearance =
active transport + glomerular filtration - passive diffusion
bile formation
○ Bile forms in hepatocytes and is secreted into the canaliculi
- Drains into bile duct then into duodenum (also stored in gall bladder) - Biliary transporters eliminated large, polar molecules (inclduing drug conjugates) into the faeces
