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Memebranes are a detmining factor for which LADME processes?
Properties of membranes: hepatocytes, blood-brain-barrier, renal tubule
Transport is highly dependent on lipophilicity, charge, and molecular weight (although fenestrae in liver capillaries do allow some drugs to sift through)
Properties of membranes: nasal mucosa, buccal mucosa, G.I. tract, Lung
- Transport affected by lipophilicity, charge, and molecular size
- Nasal mucosa generally more porous than GI tract
These membranes are slightly more porous and leaky, thus better for small molecules
Properties of membranes: blood capillaries and renal glomerulus (except for testes, placenta, and most of the CNS)
- Transport depends on lipophilicity, charge, and molecular size (up to 5000 MW)
- for larger molecules, charge becomes more important, with negative charged molecules showing lower permeability.
How to measure LogP
drop the drug in 50/50 solution of n-octanol and water.
log ([drug in n-octanol]/[drug in water])=logP
Anything over 1 is considered to be lipophillic
Lipophilicity of functional groups
note that amino acids will always be charged in the body, even though they may be zwitterionic
in order of decreasing lipophility
Important cyp enzymes and what they do for uetrecht's section
- CYP2D6-positive molecule that needs a nitrogen, oxidates 5 or 7 angstroms away
- CYP3A4- most compounds, especially large ones
- CYP2E1-ethanol (thus OH's)
pH values of stomach intestine plasma
- Law of passive diffusion
- Relates area, concentration gradient and thickness to the rate of diffusion
- V=-D* A* (C1-C2)/ dx
- where D is the diffusion coeffecient
- A is the surface area
- C1 is higher concentration, C2 is lower concentration
- Dx is thickness
Permeability Co-effecient (Fick's Law)
Where D is the diffusion co-effecient from Fick's law, and dx is the thicknes
flux= rate/unit area, can be solved for easily by:
- J= Peff *dC
- where J is flux, Peff is permeability coeffecient, and dC is the change in concentration (C1-C2)
P-glycoprotein is a gene product of
Multridrug resistant protein 1: MRP1
Apical Vs Basolateral location of transporters
- Apical: faces the lumen
- Basolateral: faces the blood
Transcellular vs Paracelular
- Trans: through the cell
- Para: between the cells
In drug-protein binding, what does the number of binding sites change?
Changes the binding capacity (Cbound), but does not change the rate of binding.
What is the definition of Km? (Michaelis-Menten equation)
Substrate concentration at half Vmax
According to Michaelis-Menten, what is the simplified rate at high substrate concentration, and the simplified rate at low substrate concentrations?
low [S]: v=Vmax * [S] / [Km]
high [S]: v=Vmax
use the michaelis menten equation and simplify terms. Note that high substrate is indicative of zero order kinetics, and high substrate is indicative of first order kinetics
Properties of competitive inhibition
- Km=will be come larger
- Vmax=will remain unchanged
- Remember that high [substrate] can overcome any competitive inhibition because the percentage of inhibited enzymes will decrease as substrate concentration increases.
Properties of non competitive inhibition
- Vmax is reduced by non-competitive inhibitors
- Km is unaffected
What is the unstirred water layer?
Glycocalyx (sugar side chains) that are found on the microvilli of intestines.
Are problematic for absorption of very lipophillic compounds
How is gastric emptying and intestinal motility related to absorption?
Gastric emptying is fast (0.5 to 1.5 hours), thus minimal absorption can take place.
Intestinal transit takes much longer, thus more time for absorption .
Define/explain reserve length
Anatomical length over which absorption can occur, minus the length at which absorption is complete.
A longer reserve length indicates better absorption.
4 properties unique to the small intestine
- Large surface area
- unstirred water layer
Speed of reaction for dehalogenation (from slowest to fastest)
F, Cl, Br, I
Rate of hydrolysis in COXH groups (ester, thiolestes, sulfoesters)
OATP2B1 and OATP1A2
- located on apical side of enterocytes and hepatocytes (1a2 is also located on apical side of kidneys) and important in absorption
- apical multispecific organic anion transporter
- transports endogenous and xenobiotic compounds
- endogenous: estrone sulfate, taurochlorate
- xenobiotic: statins (very important for this reason)
- inhibited by grapefruit juice.
MDR1 or P-gP
- apical gut,renal, billiary, efflux transporter
- basolateral in brain
- ubiquitous transporter
- lipophillic compounds, and lots of anti-cancer drugs
- vinblastine, vincristine, digoxin (thus important to see if new drugs will affect P-gp), antihypertensives (verapamil, propanolol), anthracyclines
- apical gut efflux transporter as well as canalicular efflux transporter as well as kidney apical efflux transporter
- CONJUGATES (GSH, sulfation, glucoronidation)
- STATINS (pravastatin, cerivastatin)
- ACE inhibitors (enalapril)
- vincristine (same as p-GP)
- apical efflux transporter in gut, kidney (brush border), and liver (canicular) and basolateral efflux transporter in brain (much like p-GP)
- sulfate conjugates (prototypical ones are estrone sulfate)
- some anti cancer drugs(mitoxantrone, topotecan and vinblastine[like p-gp])
Optimal logP values
- mostly around 1.3-2.5
- sublingual is about 5.5
How do formulations and dosage forms change according to logP
- below 0: injectable
- 0-3: oral
- 3-4: transdermal
- 4-7: toxic buildup in tissue
What are the parameters in Lipisnki's rule of 5
- Hydrogen bonds<5
- H-bond donors(OH or NH) <5
- H-bond acceptors (O: or N:) <10
What are two other offshoots from Lipinski's rule of 5, and which one is best for potential drugs
- Lead-likeness (best one)
What are 5 predictors of drug absorption (orally)
- 1. good water/lipid solubility
- 2. Not much ionized
- 3. stable in acidic medium
- 4. presence of transporters
- 5. lack of efflux transporters/metabolism
Name some factors that can increase GI motility
Name some factors that can decrease GI motility
- anticholinergics (atropine, propantheline)
Name three drugs that can increase/decrease motility of GI tract (2 that decrease, one that increases)
- metoclopramide (increases GI motility)
Rate limiting steps for various types of drugs
- Unstirred water level: for verylipophillic drugs
- Membrane: for hydrophillic/transport requiring drugs
- Bloowflow: for good water/lipid soluble drugs
- monocarboxylic acid transporter
- simple carboxylic acids (salicylic acid, benzoic acids) (literally like one ring and a carboxylic acid, maybe two,anything bigger won't be a substrate)
- apical absorption transporter in gut
- organic cation transporter
- small monovalent organic cations (ex. PAEB)
- antivirals (like acyclovir)
GI absorption apical side, as well as renal absorption basolateral side and hepatic absorption sinusoidal (basolateral) side
NT1 and NT2
- transport endoneous compounds and their drug alterations
- apical absorption on enterocytes and kidney brush border and absorption at sinusoidal membranes (NT1-5)
- NT1 (purine) NT2 (pyrimidine)
- nucleoside transporter
- NT1 (allopurinol, azathioprine)
- NT2 (5-fluorouracil)
- sodium phosphate transporter
- apical absorption on enterocytes
- fosfomycin (antibacterial)
- foscarnet (antiviral)
Vascular binding proteins and what they bind to
- Albumins (WA+ WB)
- a1-acid glycoproteins (WB)
What are the factors that govern rate and extent of drug distribution?
- 1.Vascular binding and tissue binding- extent of distribution
- 2. Blood flow to tissues - rate of distribution
- 3. Presence of barriers (BBB,CSF,placenta)
- 4. presence of transporters (influx/efflux)
Liver transporters on the sinusoidal membrane (basolateral)
- all influx :
- MCT2 (simple carboxylic acids)
- OATP (1B1,1B3,2B1)(takes in bile acid + bilirubin)
- NTCP (takes in bile acid, and some statins)
Liver transporters on canalicular membrane of hepatocytes
- all efflux
- MRP2 (excretes bilirubin)
- BSEP (excretes bile acids)
- sodium dependent taurocholate cotransporting polypeptide
- found on sinusoidal membrane, involved in absorption
- transports bile acids (taurocholate, cholic acid)
- transports statins (pitavastatin, rosuvastatin, atorvastatin)
- anions (estrone sulfate, bromosulfophthalein)
- Sinusoidal transporter in hepatocytes, involved in absorption
- Quite promiscuous transporter
- Endogenous: taurocholate, bile acids, bilirubin
- Anions: estrone sulfate, ACE inhibitors, statins, bromosulfophthalein
- Steroids: ouabain
- cations: quarternary ammonium compounds
- sinusoidal membrane, involved in absorption
- monocarboxylic acid transporter
- note that MCT1 is located in the intestines.
- proton co-transporter
- substrates: lactate, pyruvate, benzoate, other simple carboxylic acids
- located on sinusoidal membrane and kidney basolaterally, involved in absorption
- involved in transporting larger acids (p-amminohippurate, nsaids, salicylates, cephalosporins)
found in liver and kidney basolaterally for absorption.
transports primarily small monovalent cations (usually quarternary amines)
- Bile salt export pump (ABC- thus energy dependent)
- Seen on canilicular membrane responsible for efflux.
- substrates are bile acids (taurocholic acid, cholic acid) and some statins (pravastatin, rosuvastatin)
- located apically on kidney (brush border) and liver (canliculi) and effluxes
- multidrug and toxic compound extrusion
- substrates: cationic dyes, aminoglycosides, fluoroquinolones (ciprofloxacin, doxorubicin)
Dubin Johnson syndrome
progressive familial intrahepatic cholestasis, type 1 (PFIC1)
progressive familial intrahepatic cholestasis type 2
What characteristics would make a compound an ideal marker for GFR?
- 1. filtered freely
- 2. unbound to protein
- 3. biologically inert
- 4. not secreted or reabsorbed
- 5. easily measured in plasma and urine
OAT1 and OAT3
- Located on basolateral side of kidneys, absorbs compounds into the cell from blood.
- dicarboxylic acid exchanger (tertiary transport system, seen on slide 119)
- important substrates are p-aminohippuric acid, penicillin, and probenecid
Why is p-aminohippuric acid an important marker for kidney function? What is its transporter?
Can be used to diagnose kidney function as it's almost entire cleared in one pass (Extraction ratio of 1). Thus clearance=RBF.
In this way, renal blood flow can be measured.
- found on basolateral side of kidney, involved in absorption.
- substrates are monovalent simple cations (usually quarternary amines)
- found on brush border, responsible for reabsorption.
- substrates include estrone sulfate and taurocholate
- Located on brushborder of kidney (PEPT1 also seen in liver), involved in reabsorption
- B-lactam antibiotics
- Ace inhibitors, statins, peptidomimmetic drugs (acyclovir+amino acid)
- Located on brush border in kidneys, reabsorbs
- B-lactam antibiotics and other stuff
- sodium carnitine co-transporter
- located on brush border in kidney, important in reabsorption
Ascorbic acid transporter
- located on brush border of kidney, involved in reabsorption
- sodium dependent
Inorganic sulfate ion transporter
- sodium dependent
- Located on brush border of kidney, involved in absorption
Dilates urinary drug concentration and increases urine flow rate, leading to less passive reabsorption, thus more excretion.
A substrate for PEPT1/PEPT2 in kidney reabsorption (apical side). used to illustrate active reabsorption
Fractional excretion, what do different FE values mean?
- Ratio of renal clearance to filtration clearance
- FE= Clr/(Fp * GFR)
- FE=1=net filtration
- FE<1=net reabsorbed
- FE>1= net secreted
Small hydrophillic drugs are absorbed via:
amino acid transporter
- located apically on GI for absorption
- things with peptide bonds
- amino acids
- also gabapentin, l-dopa, methyldopa
Show the oxidation of an aromatic amine, a primary aliphatic amine, a secondary aliphatic amine, a tertiary aliphatic amine
what are the substrates for acetylation? amino acid conjugation?