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Factors that affect permeability
- Drug lipophilicity (log P)
- Drug size – molecular weight/size
- Drug charge (degree of ionization) – pKa(pH partition hypothesis)
- Polar surface area
- Drug Stability
- Nature of the membrane
- Nature of the medium on either side
- Drug-Protein (transporter) interactions
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Lipophilicity of R groups
amino acid < urea < amide < hydroxyl < ester < carbonyl < ether
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Christopher Lipinski’s Rule of Five
- Molecular Weight < 500
- • log P < 5
- • Hydrogen bonding < 5
- • Hydrogen bonding donors (NH or OH) < 5
- • Hydrogen bonding acceptor (N or O) < 10
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Predictors of Drug Absorption
- 1. Good water – lipid solubility
- 2. Not much ionized
- 3. Stable in acidic medium
- 4. Presence of carriers (transporters) for absorption
- 5. Lack of efflux transporters / metabolism
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Increase GI motility
- Metoclopramide
- Alkali
- Stress
- Liquids
- Hyperthyroidism
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Decrease GI motility
- Food
- Anticholinergics (Atropine, propantheline)
- Narcotics (meperidine, morphine)
- Acids
- Surgery
- Viscosity
- Ulcers, hypothyroidism
- Exercise
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Effect of Delayed Gastric Emptyingon Various Drugs
Drugs that are unstable(labile drugs)
Drugs that are poorlysoluble
Drugs transported bycarriers
Drugs that exhibit goodwater/lipid solubility
Extent decreases for unstable, increases for poorly soluble, increase carrier, and no change to last one
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Rate Limiting Step (RLS)
- Unstirred water level: for very lipophilic drugs
- • Membrane: for very water soluble drugs and drugsabsorbed via transporters
- • Blood flow: for drugs with good water and lipid solubility
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Factors Governing Rate & Extent ofDrug Distribution
- 1. Vascular binding and tissue binding – extent
- 2. Blood flow to tissues – rate
- 3. Presence of barriers: blood brain barrier (BBB),cerebrospinal fluid barrier (CSF), placentalbarrier
- 4. Presence of transporters for influx and efflux
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Forces for Reversible Drug Bindingto Proteins
- 1. Ionic
- 2. Hydrophobic
- 3. Dipole-dipole
- 4. Van der Waals – induced dipole dipole
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Importance of Protein Binding
- Influence unbound drug (activity / toxicity,distribution and removal)
- • Fluctuation in drug concentration within therapeuticrange
- • Explain stereoselective disposition of drugs
- • Drug-drug interactions
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What molecules get distributed?
- Lipophilic, unionized, stable, appropriate molecular weight
- Permeate membrane well, substrate of influx transportersand not efflux transporters
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What drug properties are important for high extent of distribution?
- Lipophilic, unionized, stable, appropriate molecular weight
- Permeate membrane well, substrate of influx transportersand not efflux transporters
- low plasma protein binding and good tissue binding
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Bile acid is made from
Cholesterol
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Importance of Biliary Excretion
- 1. Enterohepatic circulation (EHC) of bile acids for digestion(reclaimed by ASBT in intestine, NTCP-BSEP in liver)
- 2. Formation of micelles: with fatty acids, cholesterol, lecithin,and monoglycerides due to surfactant properties
- 3. Excretion of bile acids (toxic if too much) for emulsificationof fat; and bilirubin glucuronides (toxic if too much)
- 4. Route of drug and metabolite excretion
- 5. Enterohepatic circulation (EHC) of drugs – leads toincreased duration of drugs
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Importance of Hepatobiliary Transport
- Transporters: design carrier (bile acid-cisplatin)
- Site of liver toxicity: bilirubin or bile acidaccumulation
- Drug-drug interactions
- Transporter deficiency and associated diseases◦ MRP2 deficiency: Dubin Johnson syndrome◦ BSEP deficiency: progressive familial intrahepaticcholestasis, type 1 (PFIC1)◦ progressive familial intrahepatic cholestasis type 2(PFIC2) mutation in BSEP
- Polymorphism: single nucleotide polymorphism (SNP)changes transporter function
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Estimation of GFR: Ideal Marker Traits?
- 1. Filtered freely
- 2. Totally unbound
- 3. Biologically inert
- 4. Not secreted nor reabsorbed
- 5. Easily measured in plasma and urine
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GFR markers?
- Endogenous: Blood Urea Nitrogen, creatinine
- Exogenous: Inulin
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Passive reabsorption (renal) is dependent on:
- 1. Lipophilic, nonionic species
- 2. pHurine and pKa (%non-ionic)
- 3. Urine flow rate (changes transit time in renaltubules)
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Significance of Renal Excretion
- 1. Mechanism of drug / metabolite removal
- 2. Site of action of some drugs, e.g. Furosemide
- 3. Site of drug-drug interactions• therapeutic or desired (probenecid + pencillin)• toxic or adverse (cimetidine and procainamide)
- 4. Site of toxicity, e.g. aminoglycoside –accumulate in cells
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