Pharmacokinetics Flashcards
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 ……
Transport proteins
- Uniports
- Symport
- Antiport
- Primar aktiver Transport
ABC Transporter
- large Transporter Superfamily
-> 7 Subfamilies (ABCA bis ABCG), each 1-13 members (human)
-> 50 ABC Transporter (human) - one of the oldest Transporter families (Prokaryotes - human)
- energy dependent (ATPases), transmembranic
- Cause for multidrug resistance in cancer therapy
ABC Transporter
-> P-glykoprotein (MDR1, ABCB1)
Expressionsorte: Leber, Niere, Darm, Blut-Hirn-Schranke, Blut-Placenta Schranke, Blutzellen
Ausgewählte Substrate: Zytostatika, TKI, Virustatika, Antibiotika, Antihelmintika, Antihypertensiva, Immunsuppressoren, Antidepressiva, Glukokoertikoide, Antihistaminika, Opioide, Statine
Pharmakogenetische Bedeutung bei: Ökologische Therapien, Antiinfektiöse Therapien, Psychopharmaka, veränderte Bioverfügbarkeit, verstärkte billiger Exkretion
ABC Transporter
-> BCRP (ABCG2)
Expressionsorte: Leber, Darm, Blut-Hirn-Schranke, Blut-Placenta Schranke, Blutzellen, Milchdrüse, Stammzellen
Ausgewählte Substrate: Zytostatika, TKI, Virustatika, Antibiotika, Antihypertensiva, Stadien
Pharmakogenetische Bedeutung bei: Onkologische Therapien, Verminderte Bioverfügbarkeit
ABC Transporter
-> MRP2 (ABCC2)
Expressionsorte: Leber, Darm
Ausgewählte Substrate: Zytostatika, TKI, Virustatika, Antibiotika
Pharmakogenetische Bedeutung bei: Antiinfektiöse Therapien (insbesondere Antibiotika), verminderte Absorption und Bioverfügbarkeit
Polymorphism of P-gp (ABCB1, MDR1)
P-gp genotyp correlates with Digoxin concentration
INTOXICATION
cardiac: ventricular extrasystoles, tachykardia, bradykardia, AV-block
GIT: nausea, vomiting
cerebral: headache, fatigue, insomnia, vertigo, confusion, psychosis, depression, hallucination
Blockade of P-gp (ABCB1, MDR1)
- 87y, male
Anamnese: - atrial fibrillation: Anticoagulation, Molsidomine, Digoxin (0,25 mg/d)
- ulcus: eradication of Helicobacter pylori with Omeprazole plus Clarithromycine (1000 mg/d)
Medical findings: - hospitalisation due to fall and nausea and vomiting
- lab: Digoxin plasma levels 2,8 ng/ml (therapeutic window: 0.8 - 2,0 ng/ml)
Progression: - discontinue of Clarithromycine, recovery within 3d, Digoxin (after 1w: 1,1 ng/ml)
- therapy with 500 mg Clarithromycine (-> increase of Digoxin within 2d to 3.1 ng/ml)
SLC Transporter
- 395 SLC transporters
- Organized in 52 families
- different transport functions (channels, symporter, antiporter)
- different substrats
- Predominatly facilative or secondary-active
Organic Anion Transporter (OATs, SLC22)
Organic Cation Transporter (OCTs, SLC22)
Organic Anion Transporting Polypeptide (OATPs, SLCO)
Na+-taurocholate cotransporting polypeptide (NTCP, SLC10A1)
Sodium Glucose Cotransporter (SGLT, SLC5)
Bicarbonate Transporter (SLC4)
…
SLC Transporter
-> OATP1B1 (SLCO1B1)
Expressionsorte: Leber
Ausgewählte Substrate: Antibiotika, Zytostatika, Antidiabetika, Antihypertensiva, Diuretika, Statine, Ezetimib, Fexofenadine, Digoxin
Pharmakogenetische Bedeutung bei: Lipidsenkenden Therapien
SLC Transporter
-> OATP1B2/1B3 (SLCO1B2/1B3)
Expressionsorte: Leber, Niere
Ausgewählte Substrate: Antibiotika, Antihypertensiva, Statine, Ezetimib, Fexofenadine, Montelukast
Pharmakogenetische Bedeutung bei: Immunosuppressive Therapien
SLC Transporter
-> OCT1 (SLC22A1)
Expressionsorte: Leber Niere, Darm, Lunge, Magen
Ausgewählte Substrate: Zytostaike, Antiarrhythmetika, Antihistaminika, Virustatika, Metformin
Pharmakogenetische Bedeutung bei: Typ2-Diabetes (Metformin)
The influx transporter OATP1B1 (SLCO1B1)
SUBSTRATES OF OATP1B1
Antibiotika -> Benzylpenicillin, Cefazolin, Rifampicin
Zytostatika -> Irinotecan (SN-38 Metabolit), Methotrexat
Lipidsenker -> Atorvastatin, Cerivastatin, Fluvastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatinsäure, Ezemtimib-Glokoronid
Kardiovaskuläre Pharmaka -> Bosnian, Enalapril, Olmesartan, Temocapril, Valsartan
HIV Proteaseinhibitoren -> Darunavir, Lopinavir, Saquinavir
Andere Pharmaka -> Caspofungin, Sirolimus, Atrasentan, Flavopiridol
Toxin -> Arsenal, Arsenid, Phalloidin
Endogene Komponenten -> Gallensäure, Thyroidhormone, Eicosanoide, Bilirubin
The influx transporter OCT1 (SLC22A1)
SUBSTRATES OF OCT1
Antiarrhytmetika -> Quinidin
Zytostatika/TKI -> Cisplatin, Oxalipatin, Metaiodobenzyl-guanidin, Imatinib
Antidiabetika -> Metformin
Antihistaminika -> Cimetidin, Famotidin, Ranitidin
Virustatika -> Aciclovir, Ganciclovir, Lamivudin, Zalcitabin
Endogene Komponenten -> Hormone: Progesteron, Kortikosteron, Neurotransmitter: Dopamin, Epinephrin, Histamin, Acetylcholin
Glomerular filtration rate (GFR)
Kreatin -> Kreatinin
- Creatinine only eliminated by kidneys
- by glomerular filtration (filled) and secretion (open syboles)
- Creatinine clearance is reduced by renal dysfunction
Estimation of GFR
- MDRD Formula:
GFR = 186 x (Serumcrea)^-1,154 x (age)^-0,203
- by considering serumcrea, age, race and gender
- females: x 0,742 (due to less musculature)
- validated by MDRD trial “Modification of diet in Renal Diseases” - Cockroft/Gault formula
GFR = ((140-age) x kgbw)/(Serumcrea (mg/dl) x 72)
- Females: x 0,85 due to less musculature - Determination of Creatinine clearance by measuring urine samples:
(volume (ml/d) x crea in urine (mg/dl))/(Serumcrea (mg/dl) x 24 x 60 (min/d))
NOAK levels by renal dysfunction
DOSIS ADJUSTMENT dependent on renal function
GWAS: Statins and side effects
SLCO1B1 521CC
Statin -> OATP1B1
-> CYP3A4
-> Metabolite
-> Window for statin-induced myopathy
Transport proteins -> phases
Phase 0: Influx (SLC transporter)
Phase I: Functionalisation, Oxidation (Cytochrom P450-Enzyms)
Phase II: Konjugation (UGTs u.a.)
Phase III: Efflux (ABC transporter)
-> relevancy
-> reduced influx
-> increased efflux
Clearance
Defined rate drug eliminated from the body
-> Can be defined for various organs in the body
-> Sum of all routes of elimination
-> CLtotal = CLliver + CLkidney + CLintestine
