Pharmacokinetics Flashcards
(43 cards)
Zero order kinetics
For zero order kinetics, the rate of elimination of a compound is a constant and is independent of the concentration of the chemical in the blood.
First order kinetics
For first-order kinetics, the rate of elimination of a compound is dependent on the concentration of the chemical in the blood. The higher the concentration, the more rapidly the chemical is eliminated, unless the elimination mechanisms have been saturate eliminated, unless the elimination mechanisms have been saturated. At that point, the kinetics become zero-order. This is known as saturation saturation kinetics
Half-life
The time required for the concentration of a drug in the plasma to decrease by 50 %.
Ct = C0*e^(-kt)
Ct = concentration at a certain time point
C0 = initial concentration
k = elimination constant
-> t 1/2 = ln2/k
Modification of dosage form
RASCHE WIRKUNG (cmcx high, tmax low)
- Mikronisierung
- Amorphe Wirkstoffe
- Optimaler Zerfall
- Lingualtabletten
- Lösungen
- Brausetabletten
- Tensidzusatz
VERZÖGERTE WIRKUNG (cmax low, tmax high)
- Wirkstoffeinbettung
- Matrixtabletten
- Nanokapseln
- Pellets
- Mikrokapseln
- Gerüsttabletten
- Resinate
Bioavailability
Fabs = 100 * (AUCpoDiv)/(AUCivDpo)
Frel = 100 * (AUCADB)/(AUCBDA)
Absolute bioavailability is a ratio of areas under the curves. IV, intravenous; PO, oral route. C is plasma concentration (arbitrary units).
Pharmacokinetic processes
LADME
LIBERATION
- dosage form
- particle size
- crystalline structure
- sustained release
- preparation
- food intake
ABSORPTION
- external
- membrane
- barriers
- skin
- G.I. tract
- lungs
- BBB
DISTRIBUTION
- Blood plasma <-> Tissues
- pools
- depots
- sinks
METABOLISM
- phase 1 = oxidation
- phase 2 = conjugation
EXCRETION
- Kidneys
- liver
- lungs
- saliva
- sweat
- breast milk
structural model of cell membrane
The ‘lipid sieve’ model explain how lipophilic small cpds can permeate through the membrane by passive diffusion
Hydrophilic cpds cannot permeate unless there is a specific membrane transport channel or pump.
Transfer of chemicals across membranes
- passive
- active
- facilitated
Passive transport across membranes
Passive transport determined by:
* Permeability of surface
* Concentration gradient
* Surface area
Permeability depends on:
* size
* shape
* lipid solubility
* charge of chemical
* pH of medium
* pK of chemical
lipid/water distribution coefficient
HIGH: lipophilic, solubility low and penetration high
LOW: hydrophilic, solubility high, penetration low
Factors affecting absorption
- Dissolution in the aqueous medium surrounding the absorbing surface.
- Determinants of Passive Transfer (lipid solubility, pH, pK, area, concentration gradient).
- Blood flow
Factors affecting GI Absorption
- blood flow
- motility and mixing in GI tract
- disintegration of dosage form and dissolution of particles
- chemical stability of chemical in gastric and intestinal juices and enzymes
- presence and type of food
- rate of gastric emptying
- total adsorption area
Lungs Absorption
- for gases, vapors and volatile liquids, aerosols and particles
- in general: large surface area, thin barrier, high blood flow -> rapid absorption
- influence of respiratory rate and blood flow
- blood: air partition coefficient
- blood: tissue partition coefficient
- water solubility of the chemical present in the aerosol or particle
- particle size
- diffusion distance blood/air: ca 20 mm
- total exchange gas exchange area: ca 80 m^2
Distribution
- Distribution is 3rd phase of PK process and defines where in the body a drug will go after absorption.
- Rapid process relative to absorption and elimination
- Initial (determined by blood flow) and later phases (determined by tissue affinity)
- Extent depends on:
blood flow, size, M.W. of molecule, lipid solubility and ionization plasma protein binding, tissue binding - Examples of tissues that store chemicals: fat for highly lipid soluble compounds bone for lead
- Distribution into body compartments
Plasma 3.5 l (heparin, plasma expanders)
Extracellular fluid 14 l (tubocurarine, charged polar compounds)
Total body water 40 l (ethanol)
Transcellular small: CSF, eye, fetus (must pass tight junctions)
Volume of distribution
- Chemicals appear to distribute in the body as if it were a single compartment.
- The magnitude of the chemical’s distribution is given by the apparent volume of distribution (Vd).
- Volume into which a drug appears to distribute with a concentration equal to its plasma concentration
Vd = Amount of drug in body / concentration in plasma - examples of apparent Vd’s for some drugs
Sulfisoxazole 0.16 L/kg 11.2 L/70 kg
Phenytoin 0.63 L/kg 44.1 L/70 kg
Phenobarbital 0.55 L/kg 38.5 L/70 kg
Diazepam 2.4 L/kg 168 L/70 kg
Digoxin 7 L/kg 490 L/70 kg
Phase I Metabolism
OXIDATIONS
- Cytochrome P450 enzymes (CYP)
- Flavin dependent Monooxygenases (FMO)
- Monoaminoxidases (MAO)
- Cyclooxygenases (COX)
Cytochrom P450 Genfamily
- A heme-containing cytochrome protein located in ER, and is involved in electron transport
- Highly conservative, occur in most plants and animals: Human, Molluscs (Muscheln), Bacteria, Nematodes, Yeasts, Fungi, Insects, Plants
Nomenclature: CYP3A4*15A-B
- Family: 55% sequence homology
- Subfamily: 40 % sequence homology
- Isoenzyme
- Allele
Relevance of CYP P450 for drug metabolism
Specific substrates of different CYP
- CYP 1A2: verapamil, imipramine, amitryptiline, caffeine (arylamine N-oxidation)
- CYP 2A6: nicotine
- CYP 2B6: cyclophosphamid
- CYP 2C9: diclofenac, naproxen, piroxicam, warfarin
- CYP 2C19: diazepam, omeprazole, propanolol
- CYP 2D6: amitryptilione, captopril, codeine, mianserin, chlorpromazine
- CYP 2E1: dapsone, ethanol, halothane, paracetamol
- CYP 3A4: alprazolam, cisapride, terfenadine
Polymorphism: Effects on Pharmacokinetics
PM: Enzymfunktion ist fehlend und extrem langsam -> 7 %
IM: Enzymfunktion ist herabgesetzt und der Metabolismus ist langsam -> 5-10 %
EM: Enzymfunktion ist normal und der Metabolismus ist normal -> 80 %
UM: Die Enzymfunktion ist gesteigert und der Metabolismus ist extrem schnell -> 2-3 %
CYP P450 polymorphism
- codeine is metabolized to Morphine via CYP2D6
- Analgesia after Codeine is due to Morphin’s efficacy
- in contrast to extensive metabolizers (EM), poor metabolizers (PM) are characterized by a deficient efficacy of CYP2D6
Pharmacokinetics, - genetics of Tamoxifen
- Compared to Tamoxifen, the affinity of Endoxifen at ER is 100-fold higher
- Paroxetin, Fluoxetin,… Poor Metabolizer -> SERM -> growth of breast cancer cells
CYP 450 Polymorphism
CYP 2B6: deficient in 3-4% of Caucasians
CYP 2C9: deficient in 1-3% of Caucasians
CYP 2C19: deficient in 3-6% of Caucasians and 15-20% of Asians
CYP 2D6: PM (5-8% Europeans, 10% Caucasians, <1% of Japaneses), UM in Africans and Orientals
CYP 3A4: less mutations
From the “Schweizerischen Bundesgericht” (Lausanne 2001)
- patient with HIV infection (34y, female)
- therapy: Videx, Zerit and Ritonavir
- strong, but not unexpected side effects: nausea, vomiting
- self-medication with Bellergal® (available only on prescription, in medicine chest as a left-over from a previous presciption from the mother).
- amputation of the right foot and toes from the left foot
- financial compensation (physician, University Hospital Kanton Waadt)* patient with HIV infection (34y, female)
- therapy: Videx, Zerit and Ritonavir
- strong, but not unexpected side effects: nausea, vomiting
- self-medication with Bellergal® (available only on prescription, in medicine chest as a left-over from a previous presciption from the mother).
- amputation of the right foot and toes from the left foot
- financial compensation (physician, University Hospital Kanton Waadt)
What happened?
Ergotamine derivative -> CYP3A4 (Ritonavir (= HIV Protease Inhibitor)) -> Ergotamine metabolites
Patient featured typical signs of ERGOTISM (hallucination, reduced blood flow, necrosis)
which were observed in the Middle Ages after eating grain which was contaminated with Claviceps purpurea.
Patient with depression
- female, 61y, HTx, mild depression, fatigue,
- no infect, no hemodynamic instability
- drugs: Cyclosporine 2x125 mg, Azathioprine 100 mg, Prednisone 7.5 mg self-medication: St.-John’s-wort 3x300 mg since 3w
- TDM: Cyclosporine 95 ng/ml, before >200 ng/ml
- hazard for acute organ rejection !!!
Other Phase I Enzymes
- Alcohol dehydrogenases (ADH)
-> (ADH 1-3) responsable (95%) for ethanol metabolism - Aldehyde dehydrogenases (ALDH)
-> ALDH 1 (Cytosol) and ALDH 2 (Mitochondria) metabolized the oxidation to acetic acid
-> Gen defect of ALDH 2 (Asiens!) Flush, nausea, vomiting - Xanthine oxidase
-> catalyzes the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid. This enzyme plays an important role in the catabolism of purines in some species, including humans. - Monoamine oxidase (Catecholamines)
- Diamine oxidase (Histamin)
- Flavine Monooxygenasen (FMO)
- Reductases, Dehydrogenases, Esterases, Epoxide hydrolases ……
