Drug Delivery Mechanisms.pdf

Drug absorption - oral Drug absorption is controlled by the epithelial cell layer. Intestinal epithelium is the major barrier for orally administered drugs. The transcellular pathway is an important route for drug absorption. Drug molecules partition into cell...

Drug absorption - oral Drug absorption is controlled by the epithelial cell layer. Intestinal epithelium is the major barrier for orally administered drugs. The transcellular pathway is an important route for drug absorption. Drug molecules partition into cell membranes (lipid bilayer) at the apical side (mucosa) to enter the cytoplasmic domain. The drug molecules partition into another cell membrane at the basolateral side into systemic circulation. Transport is typically passive (energy independent) and follows a concentration gradient (high to low) - simple diffusion through the phospholipid bilayer. This process is suited to small lipophilic compounds as molecules must penetrate the phospholipid bilayer. Lipophilic and hydrophilic Lipophilic (hydrophobic) substances that dissolve well in lipids/non-polar solvents. Hydrophilic substances that dissolve well in water/polar solvents. Like dissolves like - lipophilic molecules tend to penetrate a cell membrane due to their solubility in the lipid bilayer Very lipophilic compounds may be retained in the cell membrane How do we measure a drug’s lipophilicity? We can simulate the absorption process by shaking the drug with an immiscible mixture of a lipophilic solvent (octanol, ‘the lipid bilayer’) and a hydrophilic solvent (water, ‘extracellular/cytoplasmic fluid’). The distribution of the drug between the two layers can then be calculated. This distribution is an indicator of the drug’s lipophilicity e.g. if all of the drug is in the octanol phase then it is very lipophilic. Partition coefficient and Log P  The higher the Log P value, the more lipophilic the drug The lower the Log P value, the more hydrophilic the drug Calculating Log P Log P values – drug absorption Optimal Log P values for gastrointestinal absorption by passive diffusion (oral drugs) Very high Log P - bioaccumulation e.g. polychlorinated biphenyls (PCBs), Log P > 5 Lipinski's rules - rules of thumb that indicate the likelihood of a compound being pharmacologically active No more than 5 hydrogen bond donors No more than 10 hydrogen bond acceptors Molecular mass less than 500 Da Partition coefficient not greater than 5 An example of how Log P is altered by molecular modification – anticholinergics Categorizing drugs Most drugs ionise to some extent (weak acids or bases) and the pH of the medium will have a profound effect on Log P (the pH dependent version is known as Log D) and thus absorption. Ionized compounds are less lipophilic. Basic functional groups: amines (–NH2, NHR, NR2). Acidic functional groups: carboxylic acids (-CO2H), sulphonic acids (-SO3H), phenols (Ar-OH). The pKa for a basic drug (B) is expressed for deprotonation of its conjugate acid. Oral delivery is a very common route of administration: self administered, patient centred, cheap, absorption along whole GI tract, controlled release of drugs Formulation – pharmaceutics An oral pharmaceutical product such as a tablet contains a number of ingredients, each of which may affect drug absorption. Active Pharmaceutical Ingredient (API) – The morphology of the API (its physical state e.g., crystalline or amorphous) and particle size may affect bioavailability (i.e., how much is absorbed). Excipients – Fillers, bulking agents and ingredients added to facilitate the manufacturing process e.g., tablet release agents/lubricants such as magnesium stearate. The dosages of many drugs are quite small (milligrams) and it would be impossible to administer them without a carrier.  Bioequivalence A bioequivalence study compares the bioavailability of a drug (i.e. how much is absorbed) for two or more products. The absorption of a drug from different formulations, containing the same amount of active ingredient, may be different due to the drug release kinetics. Administration studies are performed individually on each of the comparable products. Plasma/serum drug concentrations following administration are used to calculate the pharmacokinetic parameters which are then compared. Passive targeting Example: Tumours have reduced transport of oxygen because of rapid cell proliferation, altered metabolism, and abnormal blood vessels. The tumour cell becomes hypoxic. This can be used as a drug delivery mechanism where a drug is activated at low oxygen levels. Active targeting The drug is conjugated to an antibody that is recognized specifically in the tissue of interest. Ivacaftor is used in the treatment of cystic fibrosis. It is metabolized by oxidation of the tert-butyl group. Replace hydrogen atoms with deuterium atoms A carbon-deuterium bond is stronger than a carbon-hydrogen bond slower rate of metabolism – improved pharmacokinetics lower doses improved efficacy, safety, tolerability alternative metabolic pathways may reduce toxicity