dennis paul, ph.d. department of pharmacology 504-568-4740 [email protected]
DESCRIPTION
BIOLOGICAL SYSTEM A Gastrointestinal and Hepatic Systems Regulation of Drug Transport, Absorption, Distribution, Excretion and Metabolism. Dennis Paul, Ph.D. Department of Pharmacology 504-568-4740 [email protected]. Principles of Pharmacology. Common processes and mechanisms whereby: - PowerPoint PPT PresentationTRANSCRIPT
BIOLOGICAL SYSTEM A
Gastrointestinal and Hepatic Systems
Regulation of Drug Transport, Absorption, Distribution, Excretion and Metabolism
Dennis Paul, Ph.D.Department of Pharmacology
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
Mechanisms of Drug Transport
• 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
Mechanisms of Drug Transport
– Influence of pH and pka– Weak acids are uncharged in acidic
environment– Weak bases are uncharged in basic
environment
Mechanisms of Drug Transport
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.
Mechanisms of Drug Transport
Passive diffusion of non-electrolytes:
Mechanisms of Drug Transport
The higher the Kp, the more lipid soluble, the faster the rate of transfer across biological membranes
2) Passive diffusion of electrolytes
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+]
Mechanisms of Drug Transport
2) Passive diffusion of electrolytes
Mechanisms of Drug Transport
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
2) Passive diffusion of electrolytes
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
Mechanisms of Drug Transport
- 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
Mechanisms of Drug Transport
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)
Mechanisms of Drug Transport
HA
H+ + A-
Mechanisms of Drug Transport
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
Mechanisms of Drug Transport
HB+
H+ + B
2. Filtration - Passage of molecules through membrane pores or porous structures.
Mechanisms of Drug Transport
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
Mechanisms of Drug Transport
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
Mechanisms of Drug Transport
• 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
Mechanisms of Drug Transport
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
Mechanisms of Drug Transport
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
Mechanisms of Drug Transport
5. Ion-pair transport
+
_
+ _ + _
+
_
Highly ionized
Carrier
Passive diffusion
Mechanisms of Drug Transport
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 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