Pharmacokinetics: Oral Absorption

Pharmacokinetics 2: Oral Absorption

• Oral absorption is the process by which a drug moves through intestinal tissues and enters the body's circulation system.
• This lecture covers oral absorption processes, impacting factors, drug transport mechanisms, the influence of food, and modified-release formulations.

PHAR3921 Map

• Pharmacodynamics focuses on what a drug does to the body.
• Pharmacokinetics explains what the body does to the drug.
• Pharmacogenomics studies how genes affect drug response.
• Key pharmacokinetic processes include absorption/routes, distribution, metabolism/clearance, and elimination.

Learning Objectives

• Define oral absorption and related parameters like Cmax, Tmax, AUC, and bioavailability (F).
• Describe factors and physiological barriers affecting oral absorption.
• Discuss drug transport mechanisms across cell membranes, including transcellular, paracellular, passive diffusion, and active transport.
• Describe intestinal drug transporters, using PEPT1 and P-glycoprotein as examples.
• Explain how food affects oral absorption with specific examples.
• Understand mechanisms and applications of modified-release formulations.

Routes of Administration and Formulations

• Drug administration routes include oral, buccal, sublingual, rectal, topical, inhaled, and parenteral (SC, IM).
• Drugs are formulated as tablets, capsules, or solutions, influencing how they're administered.
• The oral route involves drug absorption through the gastrointestinal tract.
• Permeability across cell membranes, physiological barriers, drug transporters, and food interactions affect oral drug absorption.

Oral Drug Absorption Process

• Oral drug administration is a complex process involving drug disintegration/dissolution in the intestinal lumen.
• It includes crossing basolateral membranes of enterocytes and first-pass metabolism in the intestine and liver.
• Drugs pass through the portal blood system and may undergo enterohepatic circulation (EHC).
• The liver metabolizes drugs before they enter systemic circulation.
• The small intestine is a primary site for oral drug absorption due to its large surface area and permeability.
• Not all drugs are fully absorbed due to the harsh GI environment and physiological barriers.

Factors Influencing Oral Drug Absorption

• Factors influencing oral drug absorption are categorized into drug-specific and patient-specific factors.
• Drug-specific factors include physicochemical properties like solubility/lipophilicity (logP), pH and pKa (ionization), particle size, and dissolution rate.
• Dosage form (excipients, solution vs. solid forms) also affects absorption.
• Patient-specific factors include physiological barriers (mucosal/cellular), gastric emptying time, and intestinal transit time.
• Other patient-specific factors include blood flow to the GI tract, degrading enzymes, first-pass metabolism/loss, and GI content (fasting/fed).

Physiological and Biological Barriers

• Lumen barriers include harsh acidic conditions in the stomach (pH 1-2.5).
• Lumen barriers also include mucin-bicarbonate barrier and GI enzymatic degradation.
• The mucosal barrier involves mucins capturing foreign substances.
• Cellular membrane permeability is affected by the phospholipid bilayer, which is less permeable to hydrophilic drugs and large molecules.
• Drug transport occurs via transcellular and paracellular pathways, involving specific drug transporters.

Drug Transport: Transcellular and Paracellular

• Transcellular transport is the common pathway for lipid-soluble drugs, including weak acids and bases.
• The drugs cross both apical and basolateral membranes of enterocytes through passive diffusion, active transport, or endocytosis.
• Paracellular transport plays a smaller role in drug absorption.
• Tight junctions between intestinal epithelial cells limit paracellular transport.
• Only small, hydrophilic drugs can pass through paracellular space via passive diffusion.
• Examples of drugs using paracellular transport are atenolol, cimetidine, and frusemide.

Cell Membrane Transport

• Membrane transport includes passive and active transport mechanisms.
• Passive transport includes simple and facilitated diffusion.
• Active transport includes secondary and primary active transport methods.
• Membrane transporters use electrochemical gradients or chemical energy (ATP hydrolysis).

Intestinal Absorption: Simple Diffusion (Passive)

• Simple diffusion is mainly used by lipid-soluble drugs without requiring energy or helper proteins.
• Drugs move down the concentration gradient, dependent on solubility, size, and ionization.
• Small, non-polar, highly lipid-soluble drugs like diazepam diffuse rapidly.
• Small water-soluble drugs can move through aqueous pores, such as alcohol.
• Pore transport is a passive mechanism driven by hydrostatic pressure and is paracellular.

Facilitated Diffusion

• Facilitated diffusion uses specialized proteins to move substrates across the cell membrane down concentration gradients.
• Two types of proteins are channel proteins and carrier proteins.
• Channel proteins create hydrophilic passages for ions like Na+, K+, Ca++, Cl-, and water.
• Carrier proteins bind reversibly with specific substrates, change shape, and shield the drugs across membranes.
• This process is responsible for the transit of water-soluble, polar molecules and ions that are structurally similar to endogenous substances.
• Facilitated diffusion does not use energy.
• Because carrier proteins rely on the reversible binding of substrates it can be a faster process than simple diffusion but is saturable.

Active Transport

• Active transport necessitates energy from ATP hydrolysis or electrochemical gradients.
• It moves drugs against a concentration gradient (uphill).
• Active transport is selective for drugs structurally similar to endogenous substrates like ions, vitamins, and amino acids.
• The process is saturable due to the limited number of carrier proteins.
• Primary active transport involves energy for movement in one direction (uniporter), e.g., Na+/K+ ATPase pump, ABC transporters.
• Secondary active transport uses the movement of another molecule (symport or antiport).

Drug Transporters

• Drug transporters are endogenous membrane proteins that move drugs across plasma membranes.
• These transporters are concentrated in intestines, kidneys, liver, and brain tissues.
• Solute carrier (SLC) transporters function as uptake transporters via facilitated diffusion and secondary active transport.
• Examples: peptide transporter (PEPT1) and organic anion-transporting polypeptide (OATP).
• ATP-Binding Cassette (ABC) transporters need energy from ATP hydrolysis.
• They act as drug efflux transporters such as P-glycoprotein (P-gp) and multidrug-resistant protein (MRP).

Intestinal Drug Transporters Examples

• PEPT1 facilitates the uptake of beta-lactam antibiotics and ACE inhibitors.
• OATP facilitates the uptake of statins.
• MCT facilitates uptake of valproic acid.
• P-gp causes efflux of cardiac glycosides.
• BCRP causes efflux of statins.
• MRP2 causes efflux of methotrexate and ritonavir.

Mechanisms for PEPT1-Mediated Intestinal Drug Uptake

• Peptide transporter protein 1 (PEPT1) serves as the primary transporter for oral drug absorption.
• PEPT1 moves drugs against concentration gradients.
• A symporter couples to proton movement, providing electrochemical energy.
• Drugs with structures similar to dipeptides and tripeptides, like beta-lactam antibiotics and ACE inhibitors, undergo peptide transport.

P-glycoprotein (P-gp)

• P-glycoprotein (P-gp) is an ATP-binding cassette (ABC) transporter enabling active transport.
• It is expressed in the apical membrane of the small intestine.
• P-gp pumps foreign substances and is a limiting factor in intestinal drug absorption.
• Therefore, because P-gp inhibits intestinal absorption, it can affect the oral availability of substrate drugs.
• P-gp can interact with other drugs and lead to drug resistance when overexpressed.

Cyclical Mechanism of P-gp

• It consists of two halves, each having a nucleotide-binding domain (NBD1 or NBD2) and a transmembrane domain (TM1 or TM2).
• P-gp switches between inward-facing (open) and outward-facing (closed) conformations.
• In the inward-facing (open) state it has a high affinity for the substance, and once bound, the protein switches to the outward-facing (closed) conformation where it has a low affinity.
• ATP-binding at the NBD triggers a conformational transition to pump the material out of the cell.

P-gp's Effects on Absorption

• P-gp negatively impacts oral drug absorption, affecting oral drug absorption as an efflux transporter.
• Altered P-gp functionality can come from P-gp activators, inducers, and inhibitors.
• By inhibiting P-gp function, substrate drug absorption is increased.

Oral Drug Metabolism and Loss

• Oral drugs undergo first-pass metabolism upon reaching systemic circulation, particularly lipophilic drugs.
• Metabolism occurs primarily in the liver but also in the gut wall and lungs.
• Phase I CYP enzymes and Phase II enzymes mediate metabolism.
• Metabolism reduces bioavailability, leading to inadequate drug absorption.
• Drugs with substantial first-pass loss cannot be given orally, like sublingual nitroglycerin, IV lidocaine, and inhaled salbutamol.
• Some drugs can be given orally with reduced bioavailability, such as morphine (40%), propranolol (25%), and verapamil (10-20%).

Impact of Food on Absorption

• Nutrients affects drugs through GI environmental changes, where increased gastric motility can increase absorption.
• The presence of liquids lower drug concentration. As a result, reduced transit time also lowers absorption rate.
• Certain drugs need to be delivered without food because bile salts facilitate the crossing of poorly soluble drugs, like griseofulvin, across cell membranes.
• Drugs that can normally be taken with food can result in decreased absorption, too.

Effects of Fasted vs. Fed States

• It can influence oral drug absorption due to physiological changes in the GIT based on the drug's properties.
• A fasted state promotes faster time for the stomach emptying.
• Conversely, a fed state enhances the effects of bile and transit because of fats and improved blood supply.
• The presence of food and other external stimuli can result in slowed delivery.

Grapefruit Interactions

• Grapefruit can cause toxicity in patients taking CYP3A4 metabolized drugs, like simvastatin and felodipine.
• Grapefruit inhibits these enzymes in the intestinal wall and increases drug concentration.

Formulation-Based Absorption of Drugs

• Immediate Release drugs are effective quickly and enter the system rapidly. However, their effects wear off after a short time.
• Enteric coating: DR protect against acid degradation in tablets and capsules.
• Extended Release: ER or slow-release allows for lower blood contact and a slower, steadier release into blood to maintain appropriate levels for a longer time.
• MRFs: MRFs can be helpful for patients and improve consistency and adherence.

Modified-Release Advantages

• Dissolutions can assist in various release mechanisms that may suit particular drug properties.
• Enteric coated drugs can allow site specificity.
• Maximum levels can lower the total intake needed.
• Reduced dosing frequency and improved patient adherence and therapeutic consistency.