Physiochemical factors affecting Bioavailability

Question 1

How can the ionization of weak acids and bases be improved?

Answer 1

-inducing ionization by making the pH more basic or acid
-it forms an ion-dipole (charged acid, base, and H2O)

-weak acids lose H to ionize in a basic environment, bc there are bases to receive the H
-weak bases gain H to ionize ionized in an acidic environment -> there acids that donate H

Question 2

What is the ratio between acidic and basic species at a certain pH?

Answer 2

-pH 7 -> #acidic = #basic
-pH is a log scale -> pH 9 (2 fold more) -> 100x more basic species

Question 3

What does the pKa indicate?

Answer 3

-it is the pH at were the molecules are 50% ionized and 50% unionized
-property of ionizable drug (so glucose doesn’t have a pKa)

Question 4

3 things are needed to predict the ionization of a drug:

Answer 4

-weak base or weak acid?
-pKa of the drug
-pH of the medium

Question 5

How can an overdose of an acidic molecule (Salicylate) be treated?

Answer 5

-drugs get filtrated through the glomerulus, only unionized drugs will be reabsorbed and ionized drugs will be excreted through the urine
-make the pH of the urine such that the drug will be more ionized -> here make it basic bc we have an acidic drug (give the patient sodium bicarbonate)

Question 6

How can urine be made more basic or acidic?

Answer 6

-Drugs
-Ammonium chloride NH4Cl - urine acidifier
-Sodium bicarbonate NaHCO3 - urine alkalinizer

Question 7

What happens to the bioavailability of Ibuprofen (weak acid) with a pKa of 5.5 if the urine is made more acidic?

Answer 7

-in the kidney unionized drugs will get reabsorbed into the body
-> raise in AUC

Question 8

How can the Lipophilicity of a drug be measured?

Answer 8

-Partition coefficient Log P
-measure the concentration of the drug in the oil and in the water phase
-octanol used as oil phase -> it is a linear molecule with 8 lipophilic carbons and a hydrophilic head -> mimics the membrane

Question 9

Why is a log scale used to express the ratio between concentration in the oil and water phase?

Answer 9

Because there is a large variation of the ratio: 1:1, 10:1, 100:1

Question 10

Difference between log P and log D:

Answer 10

log P: measures unionized drugs

log D: measures ionizable drugs -> the ionization status of the drug will determine how much will go into the water phase
-> so the pH of the medium has to be considered

Question 11

For an acidic drug: Why dose log D drops with higher pH?

Answer 11

-high log D indicates more partitioning in the oil phase
-Because the drug will be more ionized at higher pH it will partiotionate more into the water phase -> drop in log D

Question 12

Why can log D never be higher than log P?

Answer 12

-log D takes the ionization status and the pH of the medium into consideration -> so there will be a drop when the drug is more ionized

-if the drug is not ionized it is the same as log P, because log P also measures the ratio of the partitioning of unionized drug

f.e.: Indomethacin has a pKa 4.5 -> at pH 4.5 the drug is 50% ionized and 50% unionized -> what is the log D at pH 4.5 -> shouldn’t it be 0, bc the partitioning is equal=???

Question 13

Why is too much lipophilicity not preferred?

Answer 13

-drug reflex pumps love lipophilic drugs -> throw them out of the cell
-drug binding to herG channels in the heart -> delayed polarization of the cardiac action potential
-high protein binding -> less active drug
-target of Cyp450 enzymes -> drugs getting metabolized
-less soluble

-ideal log P is between 0-5

Question 14

What is the Biopharmaceutical classification system?

Answer 14

Describes how soluble and permeable a drug is
-most marketed drugs have poor solubility and permeability and fall under the Class 4
-scientist use the classification to know on what to work on to increase the absorption of the drug

Question 15

How can highly ionized drugs be absorbed?
(Absorption works better for unionized drugs)

Answer 15

-Ionized drugs exist in an equilibrium between the ionized and unionized form

Once the small unionized gets absorbed and flushed away at the other side of the membrane, the dynamic equilibrium turns some of the ionized forms into the unionized -> that can be absorbed again

how can they exist in an equilibrium, when the drug is highly ionized (partitions to 99% into the water phase) ???

Question 16

When should a drug be taken on an empty stomach?

Answer 16

-drugs pass the stomach faster on an empty stomach
-for drugs unstable in acids (PPIs), gastric acids are less secreted in empty stomachs
-drugs that are not GI irritating

Question 17

When should a drug be taken on a full stomach?

Answer 17

-gastric emptying is delayed
-GI irritating drugs
-lipophilic drugs that need time to get emulsified
-poorly soluble drug, bc time needed to go into solution

-on the other hand too much time in the stomach is not good either

Question 18

How does gastric emptying regulate oral bioavailability?

Answer 18

-the migration motor complex is a wave that migrates through the stomach and small intestine to push the food
-> stomach content is quickly cleared on empty stomach (more motility on an empty stomach??)

Question 19

How does the state of the stomach determine how quickly a drug gets absorbed?

Answer 19

-full stomach empties slowly
-solid VS liquid: solids have a slow transit -> that’s why sometimes drugs are taken with water
-fat or carbohydrate -> fat takes more time
-relaxes or stressed -> stressed takes more time

Question 20

How can a high-fat diet improve bioavailability?

Answer 20

-for lipophilic drugs
-high-fat diets signals the liver to produce bile-salt -> to emulsify lipophilic drug
-f.e. Griseofulvin (an antifungal drug) has no absorption on an empty stomach
-Absorption through lacteals -> bypass the liver (going direct to the subclavian vein)-> avoid first-pass metabolism

Question 21

How can double peaks of drug concentration be explained?

Answer 21

-Enterohepatic recirculation -> prolonged drug exposure
-drug gets absorbed to the liver -> liver recognizes the foreign drug -> secretes it into the bile -> in the GI it gets reabsorbed again

-other reasons: irregular gastric emptying and intestinal transit; two populations of granules with a different release profile

Question 22

How aging affects bioavailability:

Answer 22

-decreased blood circulation to the liver and kidney
-higher bioavailability if the drug gets less metabolized -> reduce the dose

-for prodrugs that need to be metabolized to the active form -> increase the dose

-drugs with a narrow therapeutic index and excreted through the kidney -> reduce the dose

Question 23

How disease states affect bioavailability:

Answer 23

-Congestive heart patients with reduced blood flow to the GI system (splanchnic blood flow) -> reduced absorption -> reduced Bioavailability

-Chrohns: patches of inflamed tissues (scared tissue) interferes with the absorption of the drug

-HIV patients: achlorhydria (lack of HCl in the stomach) -> weak base drugs don’t dissolve properly in the stomach -> low availability; also they have altered GI transit and diarrhea

-Cholinergic drug and altered GI motility: increased motility with pro-cholinergic drugs may reduce the bioavailability of slowly absorbed drugs or poor water-soluble drugs -> bc they need more time to get absorbed and dissolve

Question 24

How do altered GI anatomy and grapefruit change bioavailability?

Answer 24

-Gastric resection: reducing the surface area of the stomach -> lower absorption of basic drugs

-Grapefruit juice has chemicals that interfere with Cyp 450 -> so the drug is less metabolized -> leading to potential toxicity

Question 25

What are some interactions affecting Absorption?

Answer 25

-Antacids should not be administered with tetracyclin or quinolone drugs due to chelation

-Cholestyramine adsorbs other co-administered drugs -> separate by several hours