Curve Fitting & Rate Order/Absorption- Dr. Sprowls

How does fitting a curve to raw plasma [ ] vs time data and understanding rate orders help us to extract biopharmaceutic & PK information?

Zero-Order: slope doesn’t depened on [ ]

First-Order: Slope depends on [ ]

Linear Regression:

Describes the linear relationship between an independent variable (input, X) and a dependent variable (output, y)

Non-Linear Regression:

Describes a relationship in a non-linear trajectory using a parametric model (curves) when the function is known (exponential, log, power)

Correlation Coefficient (R)

Describes the STRENGTH of a linear relationship

Coefficient Determinant (r²)

Describes VARIABILITY of the outcome that can be explained by input factor

Correlation vs Causation in Biopharm/PK

Use Equations:

Zero-Order: y=mx+b → C=Co-Ko(t)

First-Order: C=Co x e^A^Kt → ln (C)= ln(Co) - Kt

Steps to Drug Absorption

1) Disintegration

2) Deaggregation

3) Dissolution

What is Absorption?

Process involving the movement of a substance from site of administration across/through biological membranes to biological fluids.

What is the PRIMARY PK factor determining the length of time it takes for a drug to produce the desired pharmacological effect?

Absorption

What can absorption greatly impact?

Bioavailability (linear relationship)

What are our organelles and intracellular contents of our cells enclosed by?

Phospholipid Bilayer Membrane

What is the Fluid Mosaic Model?

Identified a cell as a flexible, dynamic phospholipid bilayer embedded with proteins that can move about freely.

What role do carbohydrates have in cell membranes?

Attach to proteins (glycoproteins) or lipids (glycolipis) and play a role in cell signaling/regulation.

What role does cholesterol have in cell membranes?

embedded Structural support

What can proteins act as in the cell membrane to allow for cellular communication and response to external stimuli?

Receptors

What is Cellular Homeostasis?

Properties collectively allow for coordinated maintenance of things for example like regulating ion [ ], pH and other factor essential for cellular function.

What kind of molecules can easily cross the cell membrane?

Small, polar molecules (O2, CO2)

What molecules require specific transport mechanisms to cross the cell membrane?

Larger, charged molecules (proteins, Amino Acids)

How do other molecules (Ex. Drugs) move about biological barriers?

Via Active and Passive Transport

What is passive Diffusion?

Movement of drug across a membrane WITHOUT the input of energy moving from an area of higher concentration to a lower concentration. (how must drugs move across membranes)

What is the driving force of passive diffusion for oral drugs?

INCREASED concentration on the LUMINAL side of the GI epithelium relative to the serosal (blood) side. Described by rate equation of passive diffusion: dw/dt=PAC1

How does the partition coefficient (K) impact the rate of diffusion across a membrane?

More lipid soluble a drug is, the higher the partition coefficient (Eq. K= [drug]lipid/[drug]aq )

What varies dramatically in the body?

Surface area

What area of the small intestine has the largest surface area? and Why?

The duodenal area due to its Villi and Microvilli

What kind of drugs transverse the membrane MORE EASILY?

Drugs with overall MORE LIPOPHILIC profile

What is Diffusion Coefficient (D)?

A constant that differs for all drugs, but describes the rate at which a drug diffuses across a specified area per unit of time.

What is Membrane Thickness (h)?

A contributor to the diffusion rate which is mostly constant for most site of absorption unless there’s a situation where cellular architecture presents additional challenges. (Ex: Skin & BBB)

What is the thickness of the skin?

10-20 microns

What is the thickness of GI tract?

30 microns

What is the thickness of Mucus in GI tract?

50-500 microns

What can pathological or ill-health conditions alter? (Ex: cancer, meningitis, burns)

STABILITY & INTERGRITY of biological membranes

What Impacts the degree of permeability among drugs that are weak acids and bases?

Ionization State

As a pH of a given environment may change, so will the ionization state of a given drug, reflective of both the pH of the environment and pKa of the drug itself. This is related to the which Equation?

Henderson Hasselbalch

What are the THREE important conditions in the pH-Hypoothesis where the pH is different on either side of a biological membrane.

1) Drug will be ionized to a DIFFERENT EXTENT on respective sides of the membrane.

2) The total drug concentration (ionized + unionized) will be unequal.

3) The compartment in which the drug has the GREATEST EXTENT OF IONIZATION will contain the highest amount of drug.

How do we PROTECT drugs that may be subject to degradation or cause adverse events if absorbed in the wrong anatomical region?

Enteric & Physical Coatings (Ex. PPI’s)

How do tissues & plasma proteins impact the absorption or movement of drugs across biological membranes?

…

What allows for some drugs to be actively transported from the GI lumen into the bloodstream?

Influx (uptake) transporters

What are Influx (uptake) transporters ?

Shuttle naturally occurring molecules across the GI epithelia and INTO systemic circulation. (Ex in Small Intestine use transporters for vital nutrients like = Amino Acids, Cholesterol, & Electrolytes)

What is a good example of an influx transporter?

• Glucose Transporter

• L-type amino acid transporter-1 (LAT-1, L-dopa, methyldopa)

  • (look at photo)

The rate of absorption is a dynamic process for drugs that undergo active transport into the bloodstream, meaning they follow what?

Michaelis Menton Kinetics

How can the body innately protect itself from toxic chemicals that can greatly impact absorption?

• Body has many BIDIRECTIONAL capacity transporters

How are bidirectional transporters determined if they participate in absorption or exsorption?

Determine by TOTAL FLUX and cellular needs

What is the process where the body has the ability to prevent absorption of drugs/toxic drugs by actively pushing them back into the GI lumen?

Active Efflux (ATP binding cassette) [goes against concentration gradient]

What are the two most common EFFLUX transporters?

• MDR-1 (ABCB1, P-gP)

  • BCRP (ABCB2) [aka breast cancer resistance protein]

Clinical Example of efflux transporters: Paclitaxel

• MOA: tubulin stablization

• Paclitaxel is a substrate for MDR-1 in the GI tract and activates Steroid X Receptor (SXR).

• Pacilitaxel is effluxed by MDR-1 as it moves through GI tract

• Remaining activate SXR, therefore inducing enhanced transcription of MDR-1, CYP3A4 & CYP2C8.

• Result is… Coordinated metabolism & Efflux

___1____ Dosing is the most COMMON & Popular route of administration, but can demonstrate great variability including___2____

1) Oral

2) Plasma Concentrations

Which region can drugs pass through anywhere?

Alimentary Canal

What is the most IMPORTANT site for absorption for orally administered drugs?

Duodenum

What is the total transit time for a meal to make it from the oral cavity to the anus?

Roughly 14 to 58 hours with the average being 28 hours

What is the main secretion in the oral cavity that is responsible for drug dissolution and is basis for absorption in the oral cavity?

Saliva

What type of drug is Abilify? (route)

ODT

What is ODT drugs broken down by?

Saliva (remaining pieces absorbed into GI tract)

What type of drug is Actiq? (route)

Sublingual Lozenge (lollipop)

(CANNOT CHEW)

[form of fentanyl to combat breakthrough pain in cancer patients]

What two factors prevents most drugs from being absorbed in the stomach?

• pH of stomach

• membrane thickness

What can the stomach pH be modified by?

Meals based on their chemical make-up (fats, carbs, proteins), stimulation by physiological processes, or by the presence of secondary health conditions.

How does the stomach pH affect enteric coated (EC) drugs?

Normal low stomach pH does not dissolve the EC

Higher stomach pH alter by food may dissolve the EC before it reaches the site of absorption. (= useless)

Example of EC impact

Nexium used to treat GERD and PUD is EC’d with Methacrylic acid copolymer, and needs to be taken WITHOUT FOOD

What can cause Stimulation of Acid Secretion?

• Digestion phase cephalic & gastric

• proteins

• coffee

• team

• milk

• ethanol

What can cause INHIBITION of acid secretion?

• Digestion phase: intestinal

• Fats

• Carbs

• H2RA’s

• PPI’s

• Achlorhydria

  • 
    

Why is the duodenum the major site for passive drug absorption?

Anatomy allows increase Surface Area & Blood Flow

Why can’t protein drugs be delivered orally?

Due to proteolytic enzyme

What happens to prodrugs in the duodenum?

They are hydrolyzed during absorption by carboxylesterase

Clinical example of prodrug:

Candesartan cilexetil is hydrolyzed by human carboxylesterase 2 (hCES2), powerful ARB for hypertension.

How does gastric motility impact drug absorption in the GI tract?

Once drug is given PO, GI motility will move the drug through the alimentary canal at varying rates for multiple causes, resulting in change in the amount of time a drug is at the site of Maximum Absorption.

What is the window called where drugs given PO have a period of contact with a specific point of the GI tract where the drug may be most efficiently absorbed & any point before or after that window decreases absorption dramatically.

Anatomic Window of Absorption

What dosage release form MUST completely release their API in the Anatomic Window of Absorption before GI motility moves the dosange form into the large bowel?

Controlled Release

Why does an Ingested meal have the largest impact on drug movement in the GI tract and therefore drug absorption?

Because of Migrating Motor Complex

During fasted or interdigestive state alternating cycles of activity known as MMC PROPEL the food bolus through upper GI tract and into the cecum. How many Phases are in this process?

Five total Phases!

• Phase 1-4 & Fed state

What occurs in Phase I?

Quiescence

What occurs in Phase II?

• Low Amplitude

  • Irregular contractions

What occurs in Phase III?

• Regular, High amplitude contractions

  • 
    

What occurs in Phase IV?

• Descending Amplitude

• Regular Contractions

What happens in Fed State?

• Regular, Low amplitude contractions

  • 
    

What is the rate equation for passive diffusion?

dW/dt= DK/h (AC)

Does gastric time reflect a delay in the absorption of drugs?

Yes! PO drugs rapidly make its way to the stomach & time varies to reach the duodenum

What is an example of an UNSTABLE drug that will decompose in the acid environment of the stomach?

Penicillin

What is an example of a drug that will cause IRRITATION to the mucosal membranes of the stomach if they remain in prolonged contact?

NSAIDS/aspirin (release of Prostaglandins)

Which empties from the stomach faster, solids or liquids?

Liquids

What are some things that can SLOW or DELAY gastric emptying?

1. Foods high in fat

2. Cold beverages

3. Anticholinergic drugs

What do foods high in fat do to slow emptying?

Causes pyloric splinter tightening which is physical impediment to emptying

How do cold beverages slow emptying?

Physically slow stomach contractions

How do anticholinergic drugs slow emptying?

They inhibit cholinergic signals (make stomach movements)

(Pharmacological slowing of emptying)

Why aren’t liquids and small particles (<1mm) generally retained within the stomach?

They are emptied rapidly due to SIEVE-LIKE effect of the pyloric sphincter (increase Basel pressure in the stomach)

What can cause large particles (tablets/capsules) to get delayed from emptying into the duodenum by roughly 3-6 hours?

Presence of food

What happens to meals with indigestible solids?

Delayed more and emptied in the inter-digestive phase

What does peristaltic movement in the GI tract function to do and how does it impact drug absorption?

It functions to mix contents within the duodenum and brings both food and drug into intimate contact with micro-structural anatomy of the GIT.

What is it called when a drug has sufficient amount of time in contact with the brush boarder of he small intestine to have OPTIMAL ABSORPTION?

Residence Time

Conditions that decrease the TRANSIT TIME through the GI tracts, specifically the Small Intestine, can decrease the ____1_____ of a drug, and overall decrease the ____2____. (An example of this is ___3___)

1) Residence Time

2) Absorption

3) Diarrhea

Can changes in blood flow to the GI Tract alter absorption?

YES

The splanchnic circulation receives ____% of Cardiac Output, and is ______ (increased/decreased) after meals

1) 28%

2) Increase

Any condition or period with _____ (Increased/decreased) blood flow will decrease absorption.

Decrease

High profusion through the small intestine maintains a constant _______ ________ across the GI epithelium.

Concentration Gradient

The lymphatic system plays an important role in dietary absorption of what molecules?

• Poorly water soluble drugs

• Highly lipophilic drugs

What does the gallbladder release to help emulsify drugs absorbed by the lymphatic system?

Bile Salts

Drugs absorbed by the lymphatic system are shunted into enterocytes for repackaging and systemic recirculation within what molecule? Does this avoid First Pass Metabolism?

• Chylomicrons

• Yes

What are some SPECIFIC EXAMPLES of drugs that will undergo lymphatic drug absorption?

• Halofantrine

  • Testosterone Derivatives

  • Tenarotene

  • Ontazolast

  • Vitamin D3

In regards to effects of food on GI drug absorption, the FDA recommends the use of ______ and ________ diets to examine the impact of bioavailability/bioequivalence

High calorie and High Fat diets

Common examples of how food can affect bioavailability/ absorption in GIT (6)

1) delay in gastric emptying

2) Stimulation of bile flow

3) Changes in pH of GIT

4) Increased Blood flow

5) Altered luminal metabolism

6) physiochemical make-up of meals & alterations to absorption

Griseofulvin (oral anti-fungal) has the ____(highest/lowest) absorption rate following a High Fat meal.

Highest!

Why does Griseofulin have a high absorption following a fatty meal?

The presence of high fat induces the release of BILE. This helps to solubilize the lipid heavy contents of the stomach, which INCREASES the SOLUBILITY of the lipid soluble drugs.