Quartz 5

Pharmacokinetics of Absorption

10 min read

Pharmacokinetics

Absorption: Entry of the drug to the blood stream

Mechanisms of transport:

  1. Transcellular: Penetration of the drug into the IC space to move from its apical side to its basal side (Or the other way around)
    1) The drug changes milieu in the process, it goes from EC > IC > EC which have different electrolytes concentrations and pH
    1) The ion trap mechanism of Macrolides is a transcellular transport that is blocked halfway through due to this change of milieu
  2. Vesicular: The drug is encapsulated into a vesicle made out of plasma membrane lipids, from the apical to basal side (Or the other way around). The vesicle then fuse with the cell membrane on the other side
    1. The drug stays in EC milieu the whole time (Despite passing though the cell)
  3. Paracellular: The drug passes between two cells, between their junctions
    1. The drug stays in EC milieu the whole time

Types of transport forces:

  1. Passive: Along concentration gradient, transport in two ways but statistically more in the less concentrated direction
    1. Diffusion
      1. Lipophilic (And small non ionized) drugs penetrate through the lipidic cell membrane
      2. Most important transport method (50% of total transports) because most body barriers are lipid membranes
      3. Kow: Constant of solubility of a drug in octanol (Lipophilic) over water (Hydrophilic):
        1. Kow = Solubility in Octanol / Solubility in Water
        2. The higher Kow, the more lipophilic the drug, the lower, the more hydrophilic
    2. Aqueous filtration
      1. Small hydrophilic (Including ionized) drugs penetrate through the aqueous pores, transported by the water molecules
      2. In aqueous compartments of the body such as interstitial space or endothelium of blood vessels
    3. Facilitated diffusion
      1. Drugs pass through dedicated pores that are specific to them = The door is open for them only
        1. The door isn’t open for the proteins that are bound > Transport proteins need to detach first
      2. The pores can be saturated if drugs are being transported through all the open pores at the same time > Limit in the transport rate
  2. Active: One way transport against concentration gradient by consuming ATP. Transport is dedicated and saturable (Like in facilitated diffusion). Used for drugs with structural similarities with Sugars, Amino Acids and Nucleosides.
    1. Direct: With ATPase pump
    2. Indirect: With cotransporter, the other transporter molecule goes in along its concentration gradient and drives the drug’s active transport. The other molecule’s gradient is maintained by an ATPase pump
      1. The transport can be saturated by the ATPase pump rate, the cotransporter rate, or the ATP availability

Acid-Bases:

  1. pK shows at which pH value of a solution the drug will be in equilibrium (50:50) between ionized and non ionized form
    1. High pK indicates the drug is basic and will be mostly in protonated (BH+) form in blood plasma (at pH 7.4)
    2. Low pK indicates the drug is acidic and will be mostly in deprotonated form (A-) in the blood plasma (at pH 7.4)
  2. Ionized forms (BH+ and A-) are polar, which make them lipophobic = Can’t penetrate lipid membranes
    1. Ion trapping: By passing from EC to IC milieu, certain drugs change to an ionized form due to the different pH ant can’t diffuse back out of the cell as they have become ionized > They concentrate intracelularly
    2. Weak acidic drugs are ionized (Deprotonated and polar A- form) at blood plasma pH (7.4), but they will be mostly un-ionized (Protonated and apolar AH form) at stomach pH (3.4) > Can diffuse intracellularly in that apolar form
      1. Acidic urine also favorizes the reabsorption of weak acidic drugs from the urine (Pharmacokinetics of Excretion)

Active transporters:

  1. ATP Binding Casette ABC transporters:
    1. P-Glycoprotein PGP-1 (Defective in certain dog breeds like Collies) of the Blood Brain Barrier BBB: To pump Ivermectin out of the Brain
      1. Coded by the ABCB1 = MDR1 gene
    2. ABCG2 (Defective in certain Cats) of the Blood Retinal Barrier: Efflux pump normally protecting from the retinal damages from Fluoroquinolones
      1. Coded by the Breast Cancer Resistant Protein gene = ABCG2 gene
    3. Multidrug Resistance Protein coded by ATP Binding Casette C ABCC gene
  2. Solute Carrier SLC transporters:
    1. Influx or Efflux pumps
    2. Mostly involved in elimination of the drugs in the kidneys:
      1. Organic Anion Transporters OATs
        1. SLC22A12 gene codes: Urate Transporter 1 URAT1 = Organic Anion Transporter 4-Like OAT4L
      2. Organic Cation Transporters OCTs

Endocytosis:

  1. Phagocytosis: Plasma membrane folds protrude out of the cell to encapsulate large particles in the EC milieu to transport it inside of the cell in a large vesicle called Phagosome where it is digested
  2. Pinocytosis: Plasma membrane invaginates on contact with small particle to form a small vesicle and transport the particle inside of the cell
  3. Nanomedicines: Drugs are transported in an artificial structure similar to the plasma membrane to fuse with the plasma membrane and release the drug inside of the cell
    1. Structures: Liposome, Micelles, Dendrimer, Nanogel, Nanocapsule, Nanosphere
    2. Used to transport drugs that wouldn’t be able to penetrate the cells by themselves (Ex: Large polar molecules)

Drug absorption: Entry of the drug to the blood stream

  1. Does not apply to IntraVeinous IV administration (As the entry is instantaneous and maximal)
  2. Bioavailability (F value):
    1. Concentration of the drug in the blood plasma evolving with time
    2. High F: High absorption of the drug through a given route > Most of the drug is absorbed and is transferred in the blood stream
      1. Good for systemic treatments
    3. Low F: Low absorption of the drug through a given route > Most of the drug stays in the administration compartment, only a small portion is transferred in the blood stream
      1. Good for local treatment
    4. Area Under the Curve AUC graphically represents the total drug exposure = The drug concentration in the blood plasma depending on time
    5. Absolute bioavailability is the comparison (Ratio) of the bioavailability of a drug through a given route (Ex: Per Os PO) compared to the bioavailability through the IV route
      1. F = (AUC po / Dose po) / (AUC iv / Dose iv) = (AUC po x Dose iv) / (ACU iv x Dose po)
        1. For a same given dose (So Dose po = Dose iv): F = AUC po / AUC iv
    6. Relative bioavailability is the comparison of the bioavailability of a drug between two given routes (Ex: PO and IntraMuscular IM)
      1. Same calculation as for the absolute bioavailability but we compare to another route than the IV route
      2. Frel = (AUC po / Dose po) / (AUC im / Dose im) = (AUC po x Dose im) / (ACU im x Dose po)
        1. For a same given dose (So Dose po = Dose im): Frel = AUC po / AUC iv
  3. Bioequivalence: Two drugs are bioequivalent if they are absorbed at the same rate (Same Pharmacokinetics properties), with the same active substance and same effects for an identical dose (Same Pharmacodynamic properties
  4. Bolus: Quick administration with a full dose (Ex: Injection)
  5. Infusion = Slow administration with a constant rate of administration (Ex: Perfusion)

Factors influencing Bioavailability:

  1. Physiochemical properties of the drug and biological membranes
  2. First pass effect: Metabolism of the drug during absorption, before it is transferred to the blood stream
    1. Net bioavailability Fnet: The fraction of the drug that reaches systemic blood circulation without being metabolized = The bioavailability of the drug after all the combined first pass effects
      1. Fnet for PO route = Absorbed Fraction (Fa) x Fraction not metabolized by the Gut epithelia (Fg) x Fraction not metabolized by the liver Hepatocytes (Fh)
  3. Species:
    1. Different GI anatomy
      1. Different gut flora
      2. Different transit time
  4. Age: Influences pH, Gut motility
    1. Calves are monogastric animals before weaning where they become ruminants: It influences the F po
  5. Other drugs or feed components:
    1. Drug-Drug interactions: Two drugs may influence each other Pharmacokinetics
      1. If they share the same teransport proteins: They are competing for the transport protein which might get saturated
        1. Once the transporter is saturated, the remaining molecules are left in the free (Unbound) form which may interact where they are not supposed to and cause toxic adverse effects
        2. It also causes stronger release of the drug the tissues which can reach too high local concentration and have toxic (Even lethal) effects
      2. pH: Proton Pump Inhibitors and Antacids increase the stomach’s pH which can influence the absorption of weak acid drugs
      3. Metabolism: Pharmacokinetics of Metabolism
    2. Feed-Drug interaction:
      1. pH: Acidic or Alkaline feeds influence the absorption of weak acid / base drugs
      2. Chelation: Tetracyclines bind Ca2+, giving them with Milk is not recommended due to the impaired absorption
      3. Stomach fullness:
        1. Food decrease the absorption of:
          1. Pimobendan
          2. Cyclosporine
          3. Robenacoxib
          4. Fenbendazole: for Horses and Ruminants
        2. Food increases the absorption of:
          1. Fenbendazole: Except for Ruminants and Horses
          2. Grizeofulvin and Posaconazole: Increased absorption with fatty meal
    3. Diseases
      1. Liver conditions decrease the metabolism and excretion of drugs > Increased bioavailability > Increased risk of overdose > Need to reduce the dose
      2. Kidney conditions impact the excretion / reabsorption of drugs
      3. GI condtions decrease the intestinal absorption of the drugs

Routes of administration:

  1. External = Topical: Application on the Skin, Mucous membranes (Including Rectum and Vagina), Eye
  2. Internal:
    1. Enteral: In the Gastrointestinal GI = Gastroenteric tract
      1. Per Os PO = Oral: Most convenient and frequent administration route
        1. Different release forms:
          1. Acid resistant capsules to prevent degradation of the drug in the stomach > Controlled release of the drug in the small intestine
        2. Can be made more palatable
        3. Can allow for mass medication: Premix for food or Powder for water
        4. Nasogastric tubes: Direct administration in the stomach, good for anorexic patients
        5. Ororuminal tube: Used to treat frothy bloat
        6. The drug is absorbed in the small intestine to the liver portal circulation where first pass metabolism occurs, then transported to the systemic blood circulation where it is delivered to the site of action
        7. The drug can be metabolized by the GI flora: Very strongly for ruminants
      2. Buccal / Sublingual: Similar to topical administration, the drug is not ingested, instead it is absorbed directly in the systemic blood circulation (Avoids liver first pass metabolism) through the vessels of the mouth mucosa / the veins under the tongue
      3. Rectal: Rapid absorption through the rectal mucosa vessels to the systemic blood circulation (Avoids liver first pass metabolism)
        1. Used for enteral drugs where the oral route is unavailable: Emesis, Unconscious, Coma, Epilepsy
          1. Diazepam can be used as rectal enema to try stopping sthe Status epilepticus (Anticonvulsives)
      4. Intraruminal / Intraabomasal injection: Extremely rare, used in reasearch
    2. Parenteral:
      1. Frequent routes:
        1. IntraVeinous IV: Directly in the blood circulation > Maximal bioavailability
        2. IntraMuscular IM: In the muscles
          1. Absorption can be influenced by the local blood perfusion of the muscle
        3. SubCutaneous SC: Under the skin
      2. Less frequent routes:
        1. Intradermal ID: Inside of the skin, used for allergy tests
        2. IntraOsseous IO: Inside of the long bones marrow, used in emergency situations where the IV route is not accessible
          1. Ex: Collapse of the circulation with no pulse > The veins are flat > Use IO administration for resuscitation drugs
        3. Intracardial / Intrapulmonar: Used for resuscitation and Euthanasia
        4. IntraArticular IA: Used frequently for Local Anesthetics, Anti-inflammatory treatment, Diagnosis
        5. Epidural / Subarachnoideal: Used for spinal cord anesthesia
        6. Perineural: Used for Local Anesthetics
  3. Special routes:
    1. Intramammary: Inside of the milk ducts, frequently used for Treatment of Mastitis
    2. Intrauterine: Used frequently for drugs influencing reproduction (Gonadal Hormones) of Cows, Ewes, Sows, Mares
    3. Inhalational: Used frequently to treat Asthma (Respiratory System)

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