Drug Absorption and Bioavailability

Terms

• A drug includes substances or mixtures of substances manufactured, sold, or presented for use in diagnosing, treating, mitigating, or preventing diseases, disorders, abnormal physical states, or their symptoms in humans or animals; or for restoring, correcting, or modifying organic functions in humans or animals.
• A pharmaceutical dosage form is a physical form of a drug, such as a solid, liquid, or gas, that allows it to be delivered in proper form to particular sites within the body, such as tablets, capsules, powders, oral solutions, and injectable solutions.
• Drug product performance is the release of a drug substance from a drug product, leading to the drug substance's bioavailability, which involves drug release, drug absorption, and drug action.
• Pharmacokinetics studies how the body interacts with administered substances throughout the exposure period, which is what the body does to the drug, involving absorption, distribution, metabolism, and excretion.
• Biopharmaceutics studies the relationships between physical and chemical properties and activity in the living body.
• Bioavailability is the fraction of a drug that reaches the blood system, it is 1 for IV (straight into circulation) and less than 1 for oral routes (first-pass effect).
• Bioequivalence compares the bioavailability of two or more formulations of the same drug.
• Pharmacodynamics studies what drugs do to the body, including their molecular, biochemical, and physiologic effects/ actions.
• Pharmacogenetics studies the effects of genetic factors on reactions to drugs.
• Toxicology studies the severe effects of drugs or chemicals.

Bioavailability Characteristics by Route

• IV = 100% bioavailability, with the most rapid onset.
• IM = 75 to ≤ 100% bioavailability, large volumes are often feasible, but may be painful.
• SC = 75 to ≤ 100% bioavailability, with smaller volumes than IM, may be painful.
• PO = 5 to less than 100% bioavailability, with the most convenient administration, but may generate a first-pass effect.
• PR = 30 to less than 100% bioavailability, with less first-pass effect than oral administration.
• Inhalation = 5 to less than 100% bioavailability, often with very rapid onset.
• Transdermal = 80 to ≤ 100% bioavailability, but very slow absorption, and used for lack of first-pass effect that creates prolonged duration of action.

Introduction to Biopharmaceutics

• Bioavailability is correlated more to drug response than amount of drug given.
• Biological samples are invasive or non-invasive samples
• Analytical methods differentiate between protein-bound or unbound parent drugs and each metabolite.
• A most direct approach to measure drug/metabolite is in blood, serum, or plasma.

ADME Interrelationship

• Dosage is absorbed, then distributed to tissues either free or bound,
• A central compartment experiences clearance, biotransformation, and excretion.
• The extent of absorption of a drug is the area under the curve.

Plasma Concentration vs Time

• MEC is the minimum effective concentration
• MTC is the minimum toxic concentration
• The therapeutic window is between the MEC and MTC
• Onset of action is the time at which the plasma concentration equals the MEC.
• The duration of action is the length of time for which the drug remains above the MEC.
• The intensity of action is the height of plasma concentration between the MEC and the maximum plasma concentration.

Drug Absorption Continued

• Blood Flow and physochemical drug characteristics affect how the drug is absorbed
• Pathology, Drug-drug interactions, and Genetics affect distribution and clearance of administered drug.
• Insufficient Systemic Absorption in the GIT is caused by: Drug stability in the GIT, drug degradation, high hepatic clearance (first-pass effect), and efflux transporters.
• Result of these factors result in poor or erratic systemic drug availability.

Oral Activity Absorption

• The following Oral Drugs are Administered locally but do not exhibit systemic absorption: Cholestyramine (Questran®) cholesterol and Mesalamine (Pentasa® or Asacol®) crohn’s.
• High first-pass effect drugs given orally: Nitroglycerin and Fentanyl
• Biotechnology derived drugs are also given parenterally (too labile in GIT)
• Extravascular route of admin, the drug must first be absorbed, transported to site of action to acquire biological/therapeutic outcome
• Systematic absorption crosses cellular membranes, and molecules cross the intestinal epithelium with different processes to reach the systematic circulation
• The permeability of the drug at the absorption site into the blood is affected by its structure and properties.

Transport Processes/Mechanisms

• Paracellular Drug Diffusion uses gaps.
• Transcellular Transport pass through cell membrane.
• Passive Diffusion flows from a region of high concentration to a region of low concentration.
• Rate of transfer is called flux
• driving force is higher drug concentrations.

Table of routes of administration

• Intravenous route offers complete bioavailability and immediate effect, but increases the chance for adverse reaction.
• Subcutaneous injection results in prompt absorption from aqueous solution, and used for insulin injection generally used for allergies and tuberculosis
• Intramuscular injection yields rapid absorption from aqueous solution, and larger volumes can be used and administered, but cause irritation
• Oral routes are the safest and easiest but may be rendered unstable through factors such as metabolism.

Enterocytes

• Line intestinal walls and have tight junctions
• Microvilli in small intestine
• Lysosome, enterocytes, microsome

Drug Transport and Bioavailability

• Requires no energy, diffuses down concentration gradient
• Carrier-mediated transport is mediated by a membrane carrier protein.
• Vesicular transport: the processes of moving molecules across cellular membranes using vesicles.
• Solutes that are Pores are responsible for transportation of those Drug molecules
• Ion Pair formation - Ionized drug + opposite charge creates neutral overall charge
• Intestinal transporters transport ions across gradient Vesicular transport: the

Oral Bioavailability

• To achieve optimal effects, dosage forms should often: withstand extreme pH changes caused by physiological environments, the presence/absense of Food, and degradative enzymes found inside an organism.
• It is important to take note of a drugs varying permeability and overall GIT motility patterns.

GIT Physiology

• Absorption usually commences at the duodenum
• Parts in the Enternal system includes the oral cavity, esophagus, and "other parts"
• Residue exits via the anus from 0.4 to 5 days
• Intrinsic factors that enhance B12 absorption
• Basic drug solubilization occurs rapidly in the stomach
• A large network of capillaries and lymphatic vessels perfuse the duodenal region and peritoneum
• Short bowel syndrome (SBS) can reduce absorptive surface area.

Factors that affect the stomach by pH levels:

• The increase in stomach interaction with enteric coated products and the absorption of fat-soluble, acid-stable drugs via passive diffusion.
• Fasted patients may also achieve rapid absorption of ethanol

Drug Dosage and Formulation

• Bioavailability of a drug can be affected by digested food contents, intestinal pH, and the substance itself.
• Dosage forms such as granules that enter the duodenum may exhibit delays resulting in dose dumping.

Key Bioavailability Facts

• Doxycycline hyclate/ Atorvastatin calcium/ Clopidogrel bisulfate decreases bioavailability with food.
• Oxycodone HCI CR/ Metaxalone/ Spironolactone tablets increases bioavailability with food.
• Gabapentin capsules/ Tramadol HCI /Digoxin/ Bupropion HCI ER have very little effect on the drug.

Presystemic Metabolism in the Intestine and Liver

• Drugs' Absolute Oral Bioavailability depends of the drugs solubility & permeability, the fraction escaping the intestine and liver metabolization of dose.
• F= Fa x Fg x Fh
• 1* (100-91/100) x (100-71/100) - 2.61%

Rule of Fives for Drug Absorption

• Rule predicts poor drug absorption or permeation is more likely where: more than 5 H-bond donors, 10 H-bond acceptors, MW is >500 Da, P calculation is >5
• methods test, biorelevance drug dissolution, scintigraphy and markers study effects of time in transit

Pharmacokinetics

• Is the study of the time course of drug absorption, distribution, metabolism, and excretion (ADME).
• Elimination includes any form of metabolism
• Distribution is what effects the blood before its broken and eliminated

Volume of Distribution

• Volume of distribution = Amount of drug in body/Conc'n of unbound drug in blood/plasma
• Total body water measures at : (0.6 L/kg) Ethanol Extra cellular water: (0.2 L/kg) Gentamicin Plasma : (0.04 L/kg) Antibodies
• Fat measures at: (0.2-0.35 L/kg) Diazepam
• Bone measures at : (0.07 L/kg) Lead and Fluoride

Key Processes

• the three functionally distinct processes, is how they enter the human body or what route

1. Plasma
2. Extracellular
3. Intracellular

Pharmacokinetic Parameters

• Clearance must equate with 0.693*Vd/t(1/t)
• Liver equates to biotransformation
• Rate (e.g. elimination) is proportional to CL x C

Pharmacokinetic Variable for Drugs

• CL x tc= 2.8 L/h/70kg x 10 mg/L
• Cl x tc/ F x dosing interval = 28 mg/h/70kg /0.96 x 12 hrs
• Vd x tc = 35L/70kg x 10mg/L

Explore drug action duration, GIT absorption factors, and therapeutic index calculation. Understand parenteral administration of biotechnology drugs and bioavailability determinants. Investigate drug absorption mechanisms and factors affecting oral absorption.