regulation of drug transport, absorption, distribution, excretion and metabolism

Regulation of Drug Transport, Absorption, Distribution, Excretion and Metabolism

Dennis Paul, Ph.D.Department of Pharmacology

[email protected]

Principles of PharmacologyCommon processes and mechanisms whereby:

• Drugs gain access to the body

• Drugs move throughout the body

• Drugs produce an effect by altering a physiological process

• Drugs are removed from the body

PharmacokineticsThe study of drug movement into, within and out of the body, which includes absorption, distribution, metabolism and elimination

•Pharmacokinetics:•Absorption: Transfer of drug from site of administration to systemic circulation •Distribution: Transfer of drug from systemic circulation to tissues•Metabolism: Alteration of drug to increase excretion from the body•Excretion: Drug movement out of the body

Routes of drug administrationAffects onset and duration of drug1) Enteral – directly into G.I. tractOral or rectal administration- safest, cheapest, most convenient- slow onset, sometimes unpredictable response

2) Parenteral – bypasses G.I. tractUsually injection, can be inhalation or topical administration- fast absorption, rapid onset, predictable response- more expensive, more difficult, painful, requires

sterile conditions

Oral route (enteral)● Advantages-Most common, convenient, painless and inexpensive way to administer a variety of drugs e.g. liquid, tablet, coated tablet etc

-GI tract a large blood rich absorbent surface

● Disadvantages-First pass metabolism Drug must pass through GI tract and liver before entering circulation and therefore are subject to metabolism meaning higher doses are given orally e.g. morphine

-Food and GI motility affects absorption – must comply with instructions e.g. with food or on empty stomach

-Can be difficult to predict percentage of active drug that reaches patient

Rectal route (enteral) Usually suppository, cream or enema e.g. aspirin,

barbituates Drug mixed with waxy substance that dissolves in the

rectum

Advantages-Reduced first pass metabolism, some rectal veins lead into direct circulation bypassing liver-Used in patients unable to take drugs orally e.g. elderly, young, unconscious

Disadvantages-Not well liked by patients-Absorption very variable so not reliable method of drug delivery

Drug Profiles

0102030405060708090

0 10 20 30 40 50 60 70 80 90 100

Time (h)

[Dru

g]

Physical PropertiesStructureLipid solubility Ionization state

Objectives

I. Mechanisms of drug transportII. Drug absorptionIII. Drug distributionIV. Drug metabolismV. Drug excretion

1.Passive diffusiona. Passive diffusion of non-electrolytesb. Passive diffusion of electrolytes

2.Filtration 3.Carrier-mediated transport

a. Active transport b. Facilitated diffusion

4.Receptor-mediated endocytosis 5.Ion-pair transport

Mechanisms of Drug Transport

Endogenous compounds and drugs

1. Passive diffusion – Low molecular weight drugs that are both water and lipid soluble dissolve in membrane and cross to the other side.

Primary means by which drugs cross membranes


• Passive Diffusion• Drugs dissolve and cross the cell membrane following

concentration gradient.

• Characteristics of drugs that use passive diffusion:● Small● Predominantly lipid soluble● Uncharged● Small water soluble molecules pass via pores


– Influence of pH and pka– Weak acids are uncharged in acidic

environment– Weak bases are uncharged in basic

environment


1. Passive diffusion

1) Passive diffusion of non-electrolytes

2) Passive diffusion of electrolytes

1. Passive diffusion

1) Passive diffusion of non-electrolytes

Lipid-water partition coefficient (Kp) - the ratio of the concentration of the drug in two immiscible phases: a nonpolar liquid (representing membrane) and an aqueous buffer (representing the plasma).

Kp can be measured. Kp = [drug] in lipid phase/[drug] in aqueous phase.

If the drug is more soluble in the lipid, Kp is higher. If the drug is more soluble in the aqueous phase, Kp will be lower.

The partition coefficient is a measure of the relative affinity of a drug for the lipid and aqueous phases.

One can control the Kp by modifying the side groups on the compound. The more C and H on the compound, the more lipid soluble, and thus the higher the Kp. The more O, S and the more water-soluble the compound, and the lower the Kp.


Passive diffusion of non-electrolytes:


The higher the Kp, the more lipid soluble, the faster the rate of transfer across biological membranes


pKa: the pH at which half of the molecules are in the ionized form and one half are in the unionized form.

pKa is a characteristic of a drug.

Henderson-Hasselbalch equations: For acids: pH = pKa + log [A-]/[HA]For bases: pH = pKa + log [B]/[BH+]




3 4 5 6 7 8 9 10 11pH

pH < pKa

Predominate forms: HA and BH+

pH > pKa

Predominate forms: A- and B

HA H+ + A- BH+ H+ + B

pH = pKa

HA = A-

BH+ = B


Only the unionized forms of the drug or the uncharged drug can pass through or across the membranes (or is transferred) by passive diffusion. - Un-ionized form acts like a nonpolar lipid soluble compound

and can cross body membranes- Ionized form is less lipid soluble and cannot easily cross

body membranes

By controlling the pH of the solution and/or the pKa of the drug, you can control the rate at which the drug is transferred


- Drugs that are weak electrolytes equilibrate into ionized and non-ionized forms in solution

- pH (H+ concentration) at site of administration and the dissociation characteristics (pKa) of the drug determine the amount ionized and non-ionized drug


ASPIRIN pKa = 4.5 (weak acid)100mg orally

99 = [ UI ]

Stomach pH = 2

BloodpH = 7.4

1 = [ I ]

Aspirin is absorbed from stomach (fast action)


HA

H+ + A-


Body compartment 1 - stomach

Body compartment 2 – blood

HApH = 2

1 0.01H+ + A-

HA H+ + A-

1 100pH = 7.4

Membrane

Acidic drug - pKa = 4.5 [ UI ]

[ UI ]

[ I ]

[ I ]

Aspirin accumulation

Strychnine not absorbed until enters G.I. tract

1 = [ UI ]

BloodpH = 7.4

99 = [ I ]

STRYCHNINE pKa = 9.5 (weak base)100mg orally

Stomach pH = 2


HB+

H+ + B

2. Filtration - Passage of molecules through membrane pores or porous structures.


The rate of filtration

a. Driving force: The pressure gradient in both sides.

b. The size of the compound relative to the size of the pore.

i. Smaller compound – transfer rapidly

ii. Larger compound – retained

iii. Intermediate compound – barrier

Lipid soluble – passive diffusion Water soluble – filtration


The rate of filtration: In biological systems: Filtration is the transfer of drug across membrane through the pores or through the spaces between cellsa. Capillary endothelial membranesb. Renal glomerulus


• Most substances (lipid-soluble or not) – cross the capillary wall – very fast• Lipid soluble and unionized – filtration and passive diffusion – at the same time

• 3. Carrier-mediated transport A. Active transport

- Goes against concentration gradient- Requires energy (ATP)- Mediated by transport carrier proteins- Drug combines with a transport protein in the

membrane and the complex can move across the membrane

a. Selectivity - not for all drugsb. One-way process – against drug concentration gradient

resulting in drug accumulationc. It can be saturated – Drug/receptor ratio – enzyme-catalyzed

reactionsd. Can be inhibited – ATP inhibitors, structural analogous

compounds


a. Carrier or receptor-mediatedb. Selective to specific molecules e.g. glucose c. It can be saturatedd. Does not require ATP e. Does not go against the concentration gradient f. Bi-directional – no drug accumulation

3. Carrier-mediated transport b. Facilitated diffusion


4. Receptor-mediated endocytosis- more specific uptake process

Drugs (peptide hormones, growth factors, antibodies, et al.) bind to their receptors on the cell surface in coated pits, and then the ligand and receptors are internalized, forming endosomes.

Receptor-ligand complex may take four different pathways:

a. Receptor recycles, ligand degradedb. Receptor and ligand recyclec. Receptor and ligand degradedd. Receptor and ligand transported


5. Ion-pair transport

+

_

+ _ + _

+

_

Highly ionized

Carrier

Passive diffusion


Pharmacokinetics: Absorption• Process by which drug

molecules are transferred from administration site to systemic circulation

• Factors affecting absorption:1. site of GI absorption2. modifications• Bioavailibility• Solubility of drug e.g. suspension absorbed

more slowly than a solution, solubility = absorbance

1. Sites of absorption through the GI tract

1) Mouth

2) Stomach

3) Small intestine

4) Large intestine

Drug Absorption

1) Mouth: a. Small amount of surface area but good blood flow –

best for potent drugs.

b. Transfer by passive diffusion – good for lipid soluble drugs.

c. pH = 6. Weak base drugs have better absorption. Nicotine pKa 8.5

Mouth GI tract pH 6 1-5Ionization less ionized ionizedAbsorption 4 times faster

d. Can bypass first pass effect.

Drug Absorption

2) Stomach: a. Moderate surface area – more than mouth, less than small

intestine.

b. Good blood supply.

c. Drugs absorbed in the stomach will experience first pass effect.

d. Transfer by passive diffusion.

e. Low pH (1-2) – ionization - Drugs that are weak acids will be absorbed better than weak base drugs.

f. Ion trapping: Accumulation of weak base drugs in the stomach.

Drug Absorption

3) Small intestinea. The primary site for most drugs.

b. Large surface area - Folds, villi and microvilli.

c. pH = 5-8.

d. Passive diffusion.

e. Absorption can also take place by active transport, facilitated diffusion, endocytosis and filtration.

Drug Absorption

4) Large intestine

a. Not important for drug absorption, if the drug is absorbed effectively in small intestine.

b. Can be a site of absorption for incompletely absorbed drugs.

c. Less absorption then small intestine – less area and solid nature of contents.

Drug Absorption

2. Factors that modify absorption in the GI tract1) Drug solubilization2) Formulation factors 3) Concentration of drug at the absorption site 4) Blood flow at the absorption site5) Surface area of absorption small intestine 6) Route of administration7) Gastric emptying 8) Food9) Intestinal motility10) Metabolism of drug by GI tract

Drug Absorption

1) Drug solubilization – breaking drugs into smaller, more absorbable particlesHydrophilic drugs - poorly absorbed - inability to cross the lipid-rich cell membrane.

Hydrophobic drugs - poorly absorbed - insoluble in the aqueous body fluids - cannot gain access to the surface of cells.

- largely hydrophobic yet have some solubility in aqueous solutions.

Solid Granules fine particles:

Solution

disintergration deaggregation

Drug Absorption

2) Formulation factors – materials added to the drug during processing can affect the solubilization of the drug.

a. Fillers – add bulk to the tablet

b. Disintegrators – cause table to break down into granules

c. Binders – hold tablet together

d. Lubricants – prevent tablet from sticking to machinery

Formulation factors - not clinically important if the drug is absorbed effectively and may have important influence on drug absorption for these drugs which are not effectively absorbed in the GI tract - influence drug’s bioavailability.

Drug Absorption

3) Concentration of drug at the absorption site

Passive diffusion

Driving force – the concentration gradient.

The higher the concentration of the drug, the faster the rate of absorption.

Drug Absorption

4) Blood flow at the absorption site

- maintain concentration gradient

Blood

Membrane

Drug Absorption

5) Surface area of absorption small intestine

Drug Absorption

6) Route of administration

GI tract – first pass effect

Drug Absorption

7) Gastric emptying

small intestine – primary site of drug absorption

Anything that delays/accelerates gastric emptying will decrease/increase drug absorption.

For all drugs - acidic, basic or neutral substances.

Drug Absorption

8) Food

High fat food – delay gastric emptying – slow absorption

Drug Absorption

9) Intestinal motility – depends on whether the drug is completely absorbed under normal condition.

a. Completely absorbed early upon entry into the small intestine, increasing intestinal motility will not significantly affect absorption.

b. Not completely absorbed before entry into the small intestine, increasing/decreasing intestinal motility will slow down/facilitate drug absorption.

Drug Absorption

10) Metabolism of drug by GI tracta. Drug metabolizing enzymes in the GI tract

b. Proteases in the GI tract

c. Microbes in the GI tract - metabolize certain drugs

- Drug metabolites are not usually absorbed.

Drug Absorption

– Bioavailability: fraction of oral dose that appears in systemic circulation.• Unless given as liquid, drug must be

released by:- Disruption of coating or capsule- Disintegration of tablet- Dispersion throughout stomach or G.I.

tract- Dissolution in gastrointestinal fluid

Absorption: Bioavailability

Absorption: Bioavailability

Pharmacokinetics: Drug Distribution• The dispersion or dissemination of

substances throughout the fluids e.g. plasma, intracellular fluids and tissues of the body.

• 2 drug forms:- free (pharmacologically active), can cross cell membranes- bound to plasma proteins (pharmacologically inactive)

Pharmacokinetics: Drug Distribution

Factors affecting distribution:- Plasma proteins- Blood flow to tissues- Specialized barriers- pH differences between plasma and tissue

compartments- Lipid solubility vs. water solubility

Drug DistributionVolume of distribution (Vd): A hypothetical volume of fluid

into which the drug is distributed.

- Water compartments in the body - three functionally distinct water compartments – plasma, interstitial fluid and intracellular fluid.

Total body water60% of body weight60% x 70 kg = 42 liters

Plasma6% of body weight4 litersExtracellular fluid

20% of body weight14 liters

Intracellular fluid40% of body weight28 liters

Interstitial volume14% of body weight10 liters

Drug Distribution

Interstitial fluid 10 L

Plasma 4 L

Intracellular28 L

Plasma compartment: Large molecular weight or binds extensively to plasma proteins - trapped in the plasma compartment – Vd = 4 liters.

Extracellular fluid: Low molecular weight, hydrophilic - able to move through fenestrae into the interstitial fluid, but cannot move across the cell membranes into the intracellular fluid - sum of the plasma water and interstitial fluid – Vd = 14 liters.

Total body water: Low molecular weight, hydrophobic - move into the interstitial fluid and the intracellular fluid – Vd = 42 liters.

Drug Distribution

Drug Distribution Regional blood flow – unequal distribution of

cardiac output

Perfusion rate: blood flow to tissue mass ratio

Higher: heart, kidney, liver, lung and brainModerate: muscle and skinLow: adipose tissue

The perfusion rate affects the rate at which a drug reaches the equilibrium in the extracellular fluid of a particular tissue.

The greater the blood flow, the more rapid the drug distribution from plasma into interstitial fluid. Therefore, a drug will appear in the interstitial fluid of liver, kidney and brain more rapidly than it will in muscle and skin.

Capillary permeability Drug transfer through capillary – filtration

a. Capillary structure: Capillary size and fenestrae size

Liver: larger fenestrae - greater filtration potentialBrain: smaller fenestrae – lower capillary permeability

Liver – slit junctionBrain – tight junction -blood-brain barrier

Drug Distribution

Specialized barriers-Blood-brain barrier (cell layer and basement membrane)To penetrate CNS drug must cross BBB, which consists of

epithelial and basement membrane cellsAre no pores, gaps etc to allow easy penetration of drugsDrug penetration of BBB relates to lipid solubility and ionizationHighly lipid soluble non-ionized drugs easily penetrate BBB to

access cerebrospinal fluid e.g. thiopentalHighly lipid insoluble and/or ionized drugs in general do not cross

BBB and do not affect CNS e.g. hexamethomium-PlacentaDrugs pass via simple diffusion governed by lipid solubility↑ lipid solubility = ↑ drug uptake by fetusMost drugs taken by mother reach the fetus e.g. alcohol

Drug Distribution

MEMBRANE MEMBRANE

Slit junctionDrugs

Liver Brain

Endothelial cells

Tight junction

Lipid soluble drugs

Large fenestrae

Small fenestrae

Blood-brain barrier

Passive diffusion Carrier-mediated transport

Drug Distribution

Slit junction

Capillary permeability Drug transfer through capillary – filtration a. Capillary structure:b. Chemical nature of the drug:

Sizes of the drugDrug structure: Hydrophobic drugs: passive diffusion – blood flowHydrophilic drugs – fenestrae - filtration

Drug Distribution

Rate of transfer from interstitial fluid into tissues

Passive diffusion, active transport and endocytosis.

Passive diffusion - the most common and quickest means

Drug Distribution

Interstitial fluid

Blood – plasma

Binding to plasma proteins - reversible

Drug Distribution

Interstitial fluid

Capillary endothelium cells

Blood

Cells and tissues

Consequence of drug binding to plasma proteins: Cannot go to its receptor at the site of actionCannot be distributed to body tissues Cannot be metabolized by enzymes Cannot be excreted from the body

Drug Distribution

- Bound drugs are pharmacologically inactive.- Drug binding to plasma protein will delay the

onset of drug action. - Drug binding to plasma proteins will

decrease the intensity of drug action.

Drug Distribution

Drug binding to plasma proteins may prolong drug action.

Reservoir of non-metabolized drug in the body

Surmin – trypanosomiasis – A single IV injection may be effective for three months.

Warfarin – 97% bound to plasma proteins and 3% free.

Drug Distribution

Types of plasma proteins: Albumin:

• The primary serum protein responsible for drug binding

• 68 kD • The strongest affinity for weak acid and

hydrophobic drugs. • 1 or 2 selective high affinity binding sites for week

acidic drugs.

Drug Distribution

Types of plasma proteins:Lipoproteins:

• Lipid-soluble drugs• The binding capacity is dependent on their lipid

content.• Binding ability of lipoproteins is VLDL > LDL >

HDL.• Patient – more free drug available for

absorption in patients with high HDL than patients with high LDL.

Drug Distribution

Types of plasma proteins:alpha1-acid glycoprotein:

• Alpha1- globulin• 44KD• One high affinity binding site and binds only basic drugs• Plasma concentration - inducible by acute injury, trauma,

and stress.• The half time: 5.5 days.• Patient with trauma taking a basic drug – side effect

Drug Distribution

More plasma proteinsLess free drug available

Drug DistributionPlasma Half-life (t1/2)Amount of time required for the concentration of a drug to fall to one half of its blood level- When half-life is short drug is quickly removed and duration

of action is short e.g. t1/2 = 1h drug mostly gone in 4-5 hours- When drug half-life is long drug slowly removed from body

and duration of action is long e.g. t1/2 = 60 h drug needs 300 h to be mostly gone from body

100% 50% 3.13%6.25%12.5%

t1/2 t1/2 t1/2

First order kinetics

t1/2 t1/2

25%

Drug Metabolism• Metabolism: Irreversible biochemical

transformation of drug into metabolites to increase excretion from the body via the kidney

- Metabolism/Biotransformation occurs mainly in the liver - Usually drug is converted to a more water soluble compound- Activity of metabolite may be different from parent compound - Metabolite usually more polar (ionized) - Metabolite usually less lipid soluble- Renal tubular absorption of metabolite - Metabolites less likely to bind to plasma proteins- Metabolites less likely to be stored in fat

Drug Metabolism

The liver is the dominant organ in drug metabolism

Organ Relative activity (%)

Liver 100Lung 20-30Kidney 8Intestine 6Placenta 5Adrenal 2Akin 1Leukocytes lowerSpleen lowerEye lowerbrain lower

Mechanisms of drug metabolism

1) Active drug inactive metabolite, most common metabolic reaction e.g. doxycyline

2) Inactive drug active drug, prodrug converted to active drug e.g. acyclovir

3) Active drug active metabolite, adds another step before excretion and prolongs drugs actions e.g. diazepam to active metabolite desmethyldiazepam

Drug Metabolism

Drug Metabolism• First pass effect

– Drugs taken orally pass through the liver before they get to the systemic circulation.

– During first pass through the liver, drug is removed by metabolism or hepatobiliary secretion.

– Phase I, oxidation, hydrolysis and reduction (non-synthetic reactions)

– Phase II, conjugation (synthetic reactions)– Forms easily excreted polar compound

Drug metabolitePhase I Phase II

excretion

If no functional group

If drug has functional group

Drug Phase II excretion

Phase I metabolism - Metabolizes drugs to creates sites for phase II metabolism

1) Oxidation (adds O) typically via simple addition of O or hydroxylation (adds H and O). Mediated predominantly via microsomal endoplasmic reticulum cytochrome P450 liver enzymes. Kidney and nervous tissue enzymes can also oxidize compounds

2) Reduction (gain of electron or H). Mediated by P450 enzymes

3)Hydrolysis (addition of water). Performed by hydrolytic enzymes called plasma esterases e.g. plasma cholinesterase

Drug Metabolism

Drug MetabolismI. Types of non-synthetic reactions1. Oxidation reactions

A. A direct insertion of a hydroxyl functional group into the drug molecule

B. Mostly by cytochrome P450C. Almost exclusively in the ERD. Broad specificity of cytochrome P450 – multiple isoforms

NADPH

NADP+

NADPHCytpchrome P450reductase P450

RH + O2

ROH + H2O

The hepatic microsomal cytochrome P450-dependent electron transfer chain

RH – drug substance

Drug MetabolismI. Types of non-synthetic reactions1. Oxidation reactions

A. A direct insertion of a hydroxyl functional group into the drug moleculeB. Mostly by cytochrome P450C. Almost exclusively in the ERD. Broad specificity of cytochrome P450 – multiple isoformsE. Types of microsomal oxidations

1) Aromatic or ring hydroxylation2) Aliphatic hydroxylation 3) Epoxidation4) N-, O-, and S-dealkylations5) N-hydroxylation (not P450) 6) N-oxidation (not P450)7) Oxidative deamination8) Sulfoxide formation9) Desulfuration

F. Non-microsomal oxidation 1) Alcohol dehydrogenase2) Aldehyde dehydrogenase3) Xanthine oxidase4) Tyrosine hydroxylase5) Monoamine oxidase

Drug Metabolism

Aromatic hydroxylation

Drug MetabolismAromatic hydroxylation

Drug Metabolism

Aliphatic hydroxylation

Drug Metabolism

Epoxidation

Drug Metabolism

Oxidative deamination

Drug Metabolism

I. Types of non-synthetic reactions

2. Reduction reactions - gain of electron or H

A. Catalyzed by reductases

B. Reductases - found in microsomes, the cytosol and microorganisms in the gut

Drug Metabolism

I. Types of non-synthetic reactions

1. Oxidation reactions – mostly by cytochrome P4502. Reduction 3. Hydrolysis

A. Breaking compounds with the addition of waterB. Primarily occur in the liver, kidney and in the plasmaC. Esterase – carry out the major hydrolysis reactions D. Amidase and expoxide hydrolases

Drug Metabolism

Hydrolysis catalyzed by esterases

Addition of H2O

Drug Metabolism

Hydrolysis catalyzed by amidases

Addition of H2O

Drug MetabolismI. Non-synthetic reactionsII. Synthetic reactions – conjugation reactionscouples agent to existing (or phase I formed) conjugation site on drug/metaboliteInvolves addition to functional groups including ethers, alcohols, aromatic amines

on drug metabolite• Glucuronidation - the most common reaction, occurs in the liver, Glucaroninc

acid combines with -OH, -SH, -COOH, -CONH groups to create glucuronide metabolites

• Sulfate conjugation - the second important reaction, catalyzed by sulfotransferases in the cytoplasma of the liver and other organs

• Acetylation - catalyzed by N-acetyltransferases. Acetic acid combines with -NH2, -CONH2 groups and aminoacids to give acetylated derivatives

• Methylation - catalyzed by methyltransferases in the cytoplasma or ER• Glutathione conjugation - Glutathione combines with -nitrate, epoxide and

sulphate groups to create glutathione conjugates• Amino acid conjugation - add naturally occurring amino acids prior to secretion

Drug Metabolism

Two pathways of conjugation reactions

Drug MetabolismFactors affecting drug metabolism 1. Age 2. Nutrition and diet3. Enzyme induction and inhibition by foreign compoundsInductionIncrease amount/activity of P-450 enzymesMany different compounds are able to alter isoenzyme activity P-450 drug metabolism and drug effecte,g, Phenobaritol stimulates CYP P-450 metabolisim of warfarin and reduces warfarin effect

Inhibition Decreases amount/activity of P-450 enzymes P-450 drug metabolism and drug effect

Drug Excretion• Excretion: The elimination of the substances from

the body unchanged or as a metabolite.1. Sites for drug excretion:

1) Kidney - Urine2) Liver – Bile 3) Skin 4) Lung5) Milk

1. Renal excretion

Glomerular filtrationDrug/metabolite filtered via glomeruli and concentrated in renal tubular fluid and excreted in urine.Protein bound drug remains in systemic circulation.

• Drugs from glomerulers into the renal tubules

• Pressure – blood flow• MW cut off = 5000• 7500 – restricted• Lipid soluble drugs – also by passive

diffusion

Drug Excretion

2. Renal excretion1) Glomerular filtration

2) Active secretion

• Two active transport systems:Organic acidsOrganic bases

• Relatively non-specific

• Unidirection – accumulation and excretion

Drug Excretion

2. Renal excretion1) Glomerular filtration

2) Active secretion

3) Passive reabsorption - Affected by urinary pH

• Unionized, lipid soluble metabolites are reabsorbed

• Ionized, lipid-insoluble metabolites excreted in urine

More ionization – more secretion

Drug Excretion

Forced alkaline diuresis

Phenobarbital – weak acidRenal tubule pH = 5 – 8 -Alkaline urine = increased weak acid excretion,

reduced weak base excretion-Acidic urine = decreased weak acid excretion,

increased weak base excretion

Bicarbonate–increase pH–ionized–faster excretionAmmonium chloride – decrease pH

3. Secretion from the liver:

Liver - Bile – intestine

• Liver: Metabolizing enzymesActive transport systems – bile capillaries

• Lipid insoluble or ionized drugs – excretion

• Lipid soluble – reabsorption from intestine to bile – transport back to the liver - Enterohepatic cycling:

Prolong drug actionConserve endogenous substances – VD3,B12, folic acid, estrogens.

Drug Excretion Kidneys Excretion

4. Pulmonary excretion

Gasses and volatile liquids

Simple diffusion from the blood into the airway

Drug Excretion

5. Sweat and saliva

Drugs or drug metabolites

Passive diffusion

Side reaction of the skin

Drug Excretion

6. Milk

Passive diffusion

Not very important for mother

May be important for infant

Drug Excretion

regulation of drug transport, absorption, distribution, excretion and metabolism

Documents

transfer of drug

barbituates drug

alteration of drug

pass metabolism drug

body drugs

percentage of active

variety of drugs

characteristics of drugs