Pharmacokinetic Processes

• Pharmacokinetics is described by four processes⁹

  • Absorption

  • Distribution

  • Metabolism

  • Excretion

    • Absorption describes a drug's movement from the site of administration into the blood.

    • Distribution represents drug translocation from the blood into tissues and ultimately cells.

    • Biotransformation (metabolism) involves a change, usually catalyzed by enzymes, in the parent drug structure which may result in a conversion of an initially inactive "drug" or "pro-drug" to the active form or more commonly, result in formation of parent drug metabolites which may or may no exhibit biological activity.

    • Excretion describes movement of drugs, including metabolites, out of the body.

      • The term elimination represents metabolism plus excretion.

        • These processes taken together affect the drug concentration at the receptor(s).⁹

Drugs and the Cell Membrane

• Movement of drugs from the site of administration to the site/sites of action require movement across cell membranes.

  • Lipophilic and Hydrophilic Drugs

    Attribution: AMBOSS:  Medical Knowledge Distilled Pharmacokinetics-Part 2:  Lipophilic and Hydrophilic Drugs 9/27/2019 AMBOSS:  Medical Knowledge Distilled Youtube Channel: https://www.youtube.com/channel/UC8xEQrU6VhJU6pDZd-GkJWg

  • Biological membranes consist of phospholipid bilayers (double sheet).¹¹ 

   

  • Lipid-Globular Protein Mosaic Cell Membrane Model¹⁰

    Attribution:  Figure 3 from Singer SJ Nicolson GL The Fluid Mosaic Model of the Structure of Cell Membranes. Science 1972 Feb 18; 175(4023):  720-731. https://pubmed.ncbi.nlm.nih.gov/4333397/

  • The cell membrane is the most important barrier for drug permeation due to the many lipid barriers separating body compartments.

  • Lipid : aqueous drug partition coefficients described the ease with which a drug moves between aqueous and lipid environments.

    • Ionization state of the drug is an important factor: charged drugs diffuse-through lipid environments with difficulty.

    •  pH and the drug pKa, important in determining the ionization state, will influence significantly transport.

      • The pH and drug pKa determine the ratio of lipid-to aqueous-soluble forms for weak acids and bases as described by the Henderson-Hasselbalch equation.

      • Uncharged form: lipid-soluble

      • Charged form: aqueous-soluble, relatively lipid-insoluble (does not pass biological membranes easily)

    • Henderson-Hasselbalch equation:  General form:  log (protonated)/(unprotonated) = pKa-pH

      For Acids: pKa = pH + log (concentration [HA] unionized)/concentration [A-] note that if [A-] = [HA] then pKa = pH + log (1) or (since log(1) = 0), pKa = pH

      For Bases: pKa = pH + log (concentration [BH+] ionized)/concentration [B] note that if [B] = [BH+] then pKa = pH + log (1) or (since log(1) = 0), pKa = pH

      The lower the pH relative to the pKa the greater fraction of protonated drug is found.  Recall that the protonated form of an acid is uncharged (neutral); however, protonated form of a base will be charged. As a result, a weak acid at acid pH will be more lipid-soluble because it is uncharged and uncharged molecules move more readily through a lipid (nonpolar) environment, like the cell membrane,  compared to charged molecules Similarly a weak base at alkaline pH will be more lipid-soluble because at alkaline pH a proton will dissociate from molecule leaving it uncharged and thus free to move through lipid membrane structures

  • A variety of lipids occur in biological membranes and other components of the membrane include specialized proteins and sugars.¹¹  

    • Three major types of lipids are associated with biological membranes: glycolipids, phospholipids, and sterols.

      • Glycolipid (left) and Sterol (right) Structure¹¹

        Left:  Glycolipid Right:  Sterol Attribution:  Figure 1 (B & C) from reference 11 (Watson H Biological membranes Essays Biochem (2015) 59, 43-70. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626904/pdf/bse0590043.pdf

      • Phospholipids involve two fatty acid chains linked to glycerol and a phosphate group.

      • Those phospholipids which contain glycerol are glycerophospholipids, such as phosphatidylcholine.¹¹ 

      •  

        Phosphatidylcholine Structure¹¹

        Phosphatidylcholine Attribution:  Figure 1 (A) from reference 11 (Watson H Biological membranes Essays Biochem (2015) 59, 43-70. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626904/pdf/bse0590043.pdf

     

Routes of Drug Administration I

• Oral Administration I

  • The most common route of drug administration is by oral ingestion.¹² 

    • "Absorption Overview"

      Attribution:   Saffarzadeh A Drug Absorption Overview https://www.youtube.com/watch?v=eya9jR3v7i8 .  (8/2012) Areo Saffarzadeh Youtube Channel:  https://www.youtube.com/channel/UCh93eqkE5oje6973bZXqM8A

    • Although there certain disadvantages such as limited drug absorption in some cases or emesis due to G.I. irritation, oral administration is considered the most convenient, economical and safest approach.

    • Following oral administration, the drug may be metabolized by enzymes associated with the G.I. microbiome, mucosa or liver prior to gaining systemic access.

      • Many factors influence the absorption of drugs from the gastrointestinal tract.

        • Factors include:

          • Absorption surface area

          • Blood flow to the area of absorption

          • Physical state of the drug (solution, suspension etc.)

          • Aqueous solubility of the drug

          • The drug concentration where absorption occurs.¹³

      • Drug absorption from the G.I. tract is mainly by passive aqueous diffusion.¹³ 

        • The driving force is the drug concentration gradient (described by Fick's Law ). 

          Fick's Law⁷

          Fick's Law describes passive movement molecules down its concentration gradient. Flux  (J) (molecules per unit time) = (C1 - C2) · (Area ·Permeability coefficient) / Thickness Where C1 is the higher concentration and C2 is the lower concentration Area = area across which diffusion occurs Permeability coefficient: drug mobility in the diffusion path For lipid diffusion, lipid: aqueous partition coefficient -- major determinant of drug mobility Partition coefficient reflects how easily the drug enters the lipid phase from the aqueous medium. Thickness: length of the diffusion path

        • Therefore, absorption is more likely when the drug is in the unionized (nonionized) form.

          • Some drugs can be described as either "weak acids" or "weak bases."

            • A weak acid becomes ionized when it loses a positively charged H⁺; by contrast, a weak base becomes ionized when it accepts a positively charged H⁺.

              • A acidic drug' s pKa when compared with the pH of the aqueous environment describes the ease by which the drug may lose a proton and become negatively charged.

                • The converse argument applies to drugs which are weak bases.

            • In the case of drugs defined as weak acids, better absorption would be predicted in a more acidic environment, such as the stomach with a pH range of 1-2.

              • Absorption the same week acid drug would be less likely ionized at the higher pH values (3-6) typical of the upper intestine.

                • The inverse of this description would apply to weak bases.¹³

            • Drugs that are weak acids or bases

              • A weak acid is a neutral molecule that dissociates into an anion (negatively charged) and a proton (a hydrogen ion).  For example:

                • C₈H₇O₂COOH  ⇄ C₈H₇O₂COO^- + H⁺

                • Neutral aspirin (C₈H₇O₂COOH) in equilibrium with aspirin anion (C₈H₇O₂COO^- ) and a proton (H⁺ )

                • Weak acid: protonated form -- neutral, more lipid-soluble

              • Weak base: a neutral molecule that can form a cation (positively charged) by combining with a proton. Example:

                • C₁₂H₁₁CIN₃NH₃⁺ ⇄ C₁₂H₁₁CIN₃NH₂ + H⁺

                • Pyrimethamine cation (C₁₂H₁₁CIN₃NH₃⁺) in equilibrium with neutral pyrimethamine (C₁₂H₁₁CIN₃NH₂) and a proton (H⁺ )

                • Weak base: protonated form which is charged and therefore less lipid-soluble.

            • Examples of drugs that are weak acids or weak bases:

              • Weak acids	pKa	Weak bases	pKa
                Phenobarbital (Luminal)	7.1	Cocaine	8.5
                Pentobarbital (Nembutal)	8.1	Ephedrine	9.6
                Acetaminophen	9.5	Chlordiazepoxide (Librium)	4.6
                Aspirin	3.5	Morphine	7.9

                 

    • Stomach and Gastrointestinal Tract Absorption

      • The stomach surface area supporting drug absorption is comparatively small, estimated at about 500 cm². ¹⁶

        • The upper intestine villi is associated with the much larger surface area estimated to be in the range of 32 m² to 200 m².^16,13

        • As a consequence of the substantial difference in surface areas, the drug absorption rate in the intestine is typically greater compared to the stomach even in the case in which the drug might be ionized (intestine) and nonionized (stomach).

      • Elevated gastric emptying favors increased drug absorption, typically.

        • Gastric emptying refers to stomach emptying with contents moving into the duodenum which depends on peristaltic waves, contraction of the antrum and reduced stomach size.¹⁸ 

          • For most drugs, increased gastric emptying rate and increased gastrointestinal motility promotes enhanced drug absorption.

            • Exceptions include digoxin and riboflavin in which elevated G.I. motility decreases rate of absorption.¹⁷

        • Rates of gastric emptying may be altered by many factors.

        • Factors Influencing Rates of Gastric Emptying¹⁷

          Food	Posture	Hormones	Peritoneal irritation	Severe pain	Diabetes
          Narcotic analgesics	Anticholinergics	Antacids	Metochlopramide	Ganglionic blocking agents	Alcohol

           

      • Gastrointestinal microbiome

        • Gastrointestinal microbiome consists of bacteria, viruses, fungi and microbial eukaryotes.¹⁵ 

        • Greater than 90% of the gut microbiota are described by members of two bacteria phyla, Bacteroidetes and Firmicutes.

        • Bacterioides biacutis

          "Bacterioides biacutis-one of many commensal anaerobic Bacteroides species in the gastrointestinal tract-cultured and blood agar medium for 48 hours. "The phylum Bacteroidetes consists of 3 large classes of Gram-negative, nonsporeforming, anaerobic or aerobic and rod-shaped bacteria."15 Image obtained from the CDC Public Health Image Library (https://phil.cdc.gov/default.aspx) Attribution:  US gov, Public Domain via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Bacteroides_biacutis_01.jpg

           

        • Bacillus subtilis (Firmicutes/Bacillota)

          "Microscopic image of Bacillus subtilis. Gram staining, magnification: 1000. The oval unstained structures or spores. Attribution: Y tambe (original uploader), CC BY-SA 3.0 <http://creativecommons.org/licenses/by-sa/3.0/>, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Bacillus_subtilis_Gram.jpg

      • The gut microbiomes is described by over 1000 distinct species with substantial differences between individuals.¹⁵