Lipophilicity and PKPD properties.pdf

Lipophilicity and PK/PD properties of drug molecules Learning objectives 1. Understand the ADME processes and mechanisms of transport of drug molecules across the lipid cell membrane. 2. How can we predict the hydrophilicity/ Lipophilicity of a drug molecule? 3. Discuss the effect of lipophilicity...

Lipophilicity and PK/PD properties of drug molecules Learning objectives 1. Understand the ADME processes and mechanisms of transport of drug molecules across the lipid cell membrane. 2. How can we predict the hydrophilicity/ Lipophilicity of a drug molecule? 3. Discuss the effect of lipophilicity on distribution of drugs in the body with special reference to the Volume of distribution of a drug. 4. Discuss the effect of pH on the gastrointestinal absorption of drugs and renal elimination. 5. Discuss the prodrug approach for increasing lipophilicity of drugs. Pharmacokinetics (ADME) Drug Bound to Plasma Protein Drug in GI Tract Drug Bound to Receptor Sites in Tissues Absorption Drug Unbound in Plasma (Free drug) Drug Administered Drug Unbound in Tissues Distribution Organs of Drug Elimination Intravenous Elimination Metabolism and/or Excretion Drug absorption Transport across cell membranes: 1. Passive diffusion process • Diffusion through lipoidal bilayer • Depends on size, concentration, polarity, degree of ionization, partition coefficient, surface area of absorption site, blood flow. • Polar hydrophilic molecules are poorly absorbed Eg: aminoglycosides (gentamycin). 2. Active transport (carrier-mediated) a transport protein is involved Active transport: a carrier mediated process Active transport involves transfer of a solute from one compartment to another through a biological membrane against a concentration gradient. A component of the cell membrane, called a carrier protein or transporter protein, helps in this process. The carrier protein complexes with the drug, takes it across the membrane, leaves the drug on the other side and the carrier returns to its original place. GI lumen Drug Blood Carrier + Drug Drug carrier complex Carrier Drug Predicting Hydrophilicity or hydrophobicity of drug molecules Hydrophilic: Are there functional groups capable of ionization or hydrogen bonding? Hydroxy groups, carboxy groups, amino groups? Sugar residues (as in Gentamycin, tobramycin)? Hydrophobic: Are there aromatic rings, alkyl chains, alicyclic rings, ethers, esters, halogens? A-D: All are structurally similar, only variation is the substituent in the ortho position of phenyl ring. compound B has no substitution in phenyl: use this as a reference. A and D contains hydrophilic functional groups. Therefore, more water soluble than B. Compound C would be more lipid soluble than B. Compound D (carboxyl ) would be more water soluble than compound A (hydroxyl) because of ionizable nature of -COOH Partition coefficient, K = solubility in lipid/solubility in water ➢ Since the cell membrane is non-polar, greater non-polar character of a drug molecule tends to increase its partition coefficient. ➢ The log of the partition coefficient is denoted as log P ➢ Partition coefficient between 100 and 100,000 is between log P of 2-5 ➢ Drug molecules with a partition coefficient ( Log P) between 2-5 are transported quickly across cell membranes. Mannitol, Log P = -4.67 K = 10 -4.67 =2.14 x 10 -5 = 1/46774 Mannitol’s water-solubility is 46000 times greater than its lipid solubility Alprazolam, Log P = 2.5 K =10 2.5 = 316 Alprazolam’s lipid solubility 316 times greater than its water solubility Bioavailability = 85% Volume of distribution (Vd) ▪ ▪ ▪ ▪ An apparent body space in which a drug is distributed. It is not a real physiological volume. Expressed as Liters or L/kg Determination of Vd: dose (iv)/Cp, or Dose (absorbed)/Cp Dose = Vd Cp (The Vd is a very useful PK parameter to determine the loading dose of a drug). ▪ Hydrophilic drugs have relatively small Vd., remains mainly in plasma compartment. ▪ Lipophilic drugs have large Vd. (Extensively distributed to tissue compartments). Benzyl Penicillin, log P=1.83, Vd = 42L Diazepam, log P=2.82, Vd=70L Quazepam, logP=4.1 Vd= 560L Gastrointestinal pH and drug absorption Stomach pH, 1-3 Most acidic drugs are unionized at this pH values. The unionized drug is absorbed. Basic drugs are ionized at this pH (protonation), not absorbed. In the intestine, the pH changes from 5-8. Acidic molecules now becomes ionized and watersoluble. Basic molecules becomes less ionized, more lipophilic and are absorbed. Drug absorption: pH-partition hypothesis • Biologic membranes are lipophilic. • Drugs diffuse through in unionized (lipophilic) form. • Most drugs are weak acids or weak bases. • Absorption is governed by degree of ionization (pH and pKa) Henderson- Hasselbach equation For a weak acid pH = pKa+ log (ionized/unionized) pH-pka= log ionized/unionized Ratio, (ionized)/(unionized) =10 (pH-pKa) Effect of pH on absorption of a weak acid from the stomach A drug with pka of 4 in gastric fluid of pH =1 Ratio of ( ionized/unionized) = 10 (pH-pKa) = 10 (1-4) = 10 (-3) = 0.001= 1/1000 ➢ (Ionized/unionized) = 1/1000, the unionized species of this acid is a 1000- fold higher than ionized form. ➢ The unionized, lipophilic form diffuse freely through lipid membrane, but polar ionized molecules do not. Therefore, high absorption of the unionized weak acid from the stomach. Weak bases will remain ionized in the stomach. They are not absorbed. Ionization and drug absorption Ephedrine, a basic secondary amine, pKa = 9.5 More ionized at pH below 9.5 Salicylic acid, the carboxylic acid has pKa of 3 More ionized at pH above 3 Ionization and drug absorption • Morphine, Atropine, Fenoprofen Morphine atropine Fenoprofen Q. Compare absorption of atropine and Fenoprofen from the stomach Crossing the blood brain barrier (BBB) Which of the above drugs is able to cross the blood brain barrier and cause drowsiness? Fexofenadine (Allegra) Will Fexofendine cross the BBB? Lipophilicity and drug absorption How to increase lipophilicity of the drug molecule? Masking or removing polar functional groups increases lipophilic character ▪ Esterification of the carboxyl group (prodrug approach) ▪ Introducing alkyl substituents ▪ Introducing halogen substituents ▪ Substitution of oxygen with Sulphur Beware! ▪ Polar groups may be involved in target binding ▪ Polar group may be required to reduce CNS side effects Prediction of Lipophilicity Temezepam and quazepam are benzodiazepines used for treatment of insomnia. Which of these is more lipophilic? Site A: Temazepam has a methyl, while in quazepam it is trifluromethyl. Trifluoro-enhances lipid solubility. Site B: Substitution of carbonyl oxygen in temazepam by sulfur in quazepam enhances lipid solubility. Site C: Temazepam has a hydrophilic –OH Log P = 2.2 t1/2 = 8-20h Intermediate acting logP = 4.1 t1/2 = 39h Long acting Site D: Quazepam has a fluorine atom instead of hydrogen in temazepam. Fluorine atom enhances lipid solubility. Thus quazepam would be predicted to be more lipophilic than temazepam. Lipophilicity and drug absorption Effect of partition coefficient on absorption of barbiturates. Barbiturates are weak acids (because of keto-enol tautomerism). 5,5’-Diethyl barbituric acid 5,Ethyl, 5’,hexyl barbituric acid Barbital(diethyl substitution, log P = 0.65 Hexethal (ethyl, hexyl substitution, log P 2) Hexethal is absorbed faster, faster onset of sedative action. The enol is acidic because of the availability of a removable proton Lipophilicity and drug absorption Introduction of Sulphur in place of carbonyl Oxygen in pentobarbital increases lipophilicity, increases brain level rapidly, used as an intravenous anesthetic. Pentobarbitone Log P=2.1 Thiopental Log P=2.85 Lipophilicity and ADME of beta blockers Atenolol, log P=0.23, Hydrophilic, Incomplete oral absorption low CNS penetration. Little metabolism, mainly excreted thorough urine. Long half-life. Polar beta blockers are cardio selective(1) Propranolol, log P=3.65, Lipophilic, well-absorbed, but high first-pass metabolism. penetrate readily in to CNS extensively metabolized, short half-life. Lipophilic beta blockers are non-cardio selective. (1 and 2) True or False? 1. Acidic drugs are relatively unionized in the stomach 2. Basic drugs remain ionized in the stomach 3. The following is one of the barbiturate group of drugs used for their sedative /hypnotic properties A. Substitution of one of the ethyl group with hexyl results in faster onset of action B. Replacing C=O with C=S makes it more hydrophilic Blocking metabolism to prolong activity Haloperidol decanoate (Haldol decanoate) Long-acting injectable antipsychotic. Monthly injections. Prodrug approach to increase lipophilicity • Prodrugs are bio-reversible derivatives of drug molecules that must undergo an enzymatic or chemical transformation in vivo to release the active parent drug which can then exert its desired pharmacological effect. • A strategy for improving physicochemical, biopharmaceutical and pharmacokinetic properties of potent drugs. • About 5-7% of marketed drugs are prodrugs. • Prodrugs are produced to increase the lipophilicity or to improve water solubility. Prodrug approach to increase lipophilicity Reasons for designing a prodrug. • Enhance lipid solubility (to enhance absorption) or water solubility. • Elimination/masking unpleasant taste associated with the drug. • Decrease metabolic inactivation/prolong duration of action. • Increase chemical stability. Prodrugs: Promoiety selection • The promoiety should be completely and easily removed after serving its function (Ester prodrugs are easily hydrolyzed after absorption). • Promoiety should be nontoxic. (i.e: Succinate or amino acids are naturally found in the body). valine • to increase water solubility of a drug (add a promoiety with a functional group that is ionizable or with numerous polar functional groups). Eg. Sod.phosphate and sod.succinate • to increase lipophilicity of a drug, add a promoiety with a functional group that possess non-polar or lipophilic groups.eg: decanoate for im depot injection. Q: What is the criteria for selection of a promoiety to increase water solubility of the drug? Q: What is the criteria for selection of a promoiety to design a long- acting product? Prodrugs to improve membrane permeability: Aminoacid ester prodrugs valine Aciclovir, an antiviral drug, (DNA Polymerase inhibitor, log P=-1.76), poor oral bioavailability(10-20%). Valaciclovir (Valtrex), an aminoacid ester prodrug,(log P=-0.3) converted to acyclovir by hepatic first pass metabolism (F=55%). Increasing drug absorption Bacampicillin(spectrobid, Pfizer), Penglobe, AstraSenica) an ester prodrug of ampicillin. bioavailability, 86% (Ampicillin=50%) Becampicillin (F=0.86) Pivalic acid Pivampicillin (F=0.92) Ampicillin (F=0.5) Pivampicillin: An ester prodrug. Converted to ampicillin and pivalic acid, Bioavailability=92% Lipid soluble esters: Increasing Duration of action Fluphenazine HCl Oral Dose: 1-20mg/day Fluphenazine decanoate Dose: 25-100 mg, DOA: 2 to 3 weeks Lipid soluble esters for depot injections. • Decreased water solubility. Formulated as suspension for IM or subcutaneous injection. • Fluphenazine is a neuroleptic: to treat patients suffering from schizophrenia. • The addition of a lipophilic fatty acid chain can drastically enhance the duration of action. • Intramuscular injection of Fluphenazine decanoate leads to a slow hydrolysis of the ester side chain. Examples of lipid soluble esters to increase DOA Estradiol valerate Haloperidol decanoate. Once monthly IM depot injection in oil to treat symptoms of menopause. Once monthly IM depot injection in oil for psychotic disorders. Lipid-soluble esters to enhance pulmonary or topical absorption Beclomethasone dipropionate . Hydrocortisone butyrate. As a As oral or nasal inhalation for asthma and allergic rhinitis. Rapidly absorbed in pulmonary tract or nasal cavity. topical cream (0.1%) for inflammation, pruritus, eczema. Increased topical penetration and potency compared to hydrocortisone 1% cream. Improving CNS delivery The BBB is a unique protective barrier to toxic and infectious substances. Also, a barrier for CNS delivery of drugs for the treatment of neurological diseases, brain tumors. Many factors control penetration of drugs across BBB: lipophilicity (for passive diffusion) molecular weight (less than 500 Da). Chemical approaches: ▪ Lipophilic analogs of lead compounds with log P values of 1.5-2.5. ▪ Lipid groups are added to the polar end of drug molecules. ▪ May offset PK properties: binding to plasma proteins, volume of distribution, metabolism Formulation approaches ▪ Lipid nanoparticles: drugs encapsulated in lipids Increasing CNS bioavailability by prodrugs Addition of one methyl group to morphine produces codeine: 10- fold higher BBB permeation. Addition of two acetyl groups to produce heroin increases BBB permeation 100- fold. Prodrugs to improve CNS Bioavailability • Dopamine is useful in treating Parkinson’s disease. It is too polar to cross the BBB. • The aminoacid, L-DOPA is actively transported by amino acid carrier pathway across the BBB and decarboxylated to dopamine. Dopamine has no such transporter. • L-Dopa acts as a prodrug . Bioavailability of Dopamine in the brain is improved dramatically. Log D 7.4 and possible impact on Pharmacokinetics logD 7.4 Impact on drug-like property Impact in vivo  1-1 High solubility, low permeability Low metabolism low Vd, low absorption and bioavailability possible renal clearance 1-3 Moderate solubility Moderate permeability Low metabolism Balanced Vd, potential for good absorption and bioavailability 3-5 Low solubility High permeability Moderate to high metabolism Variable oral absorption 5 poor solubility High permeability High metabolism Very high volume of distribution Poor oral absorption Renal excretion 1. Glomerular filtration 2. Active tubular secretion Membrane transporters mediate secretion 3. Tubular reabsorption Reabsorption is pH sensitive. Ionic species are excreted Renal Excretion & Reabsorption • The extent of Elimination or Reabsorption of a specific drug molecule depends on… ✓ ✓ pH of urine & Acidic/basic nature & pKa of the drug molecule. • Ionized form of a drug is always more readily Eliminated • Unionized form is always more readily Reabsorbed. • Therefore, a significant change in urinary pH can dramatically change Urinary Elimination profile of a drug. Renal clearance of -blockers Atenolol Less than 10% metabolized Renal clearance of beta blockers increased with decreasing log D Propranolol Extensively metabolized to 4-OH propranolol Tubular Reabsorption Reabsorption of most drugs is a passive process. Weak acids or weak bases: Reabsorption is influenced by urine pH and pKa of the drug. Urine pH varies from 4.5 to 8.0 depending on diet, pathophysiology and drug intake. The unionized, lipid-soluble drug is reabsorbed Strong acids and bases : no reabsorption Urine pH and reabsorption • Propoxyphene (pKa, 6): 50% ionized when pH = 6 • higher pH? Reabsorbed. • Ephedrine, Amphetamine: t1/2 decreased if urine is acidified. • Polar, unionized (eg: gentamycin), Renal clearance is independent of urine pH. Review Prodrugs: • Why are prodrugs designed for certain drugs? • What are the advantages of Esters and half esters as prodrugs • Cite examples of prodrugs and their specific advantages.