Alfred L George Jr MD Department of Pharmacology algeorgenorthwesternedu Drug Absorption Absorption refers to the transfer of a drug from its site of administration to the systemic circulation ID: 775623
Download Presentation The PPT/PDF document " Drug Absorption and Distribution" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Drug Absorption
and Distribution
Alfred L. George, Jr., M.D.
Department of Pharmacology
al.george@northwestern.edu
Slide2Drug Absorption
Absorption refers to the transfer of a drug from its site of administration to the systemic circulation.
Depends on route of administration
- intravenous administration does not
require absorption
Bioavailability
Bioequivalence
Slide3Factors Affecting Drug Absorption
Drug-related
Lipid solubilityWater solubilityMolecular sizeParticle sizeDegree of ionizationConcentrationFormulationInterfering substancesFood
Physiology-related
Age
Absorptive surface area
Integrity of absorptive surface
Gastric emptying time
Intestinal transit rate
Blood flow to GI tract
pH of luminal fluid
Gut microbiome
Slide4Intravenous
Transdermal
Subcutaneous
Intramuscular
InhalationSublingualOralRectal
Bioavailability
is the main criterion for choosing the route of administration
Routes of Drug Administration
Slide5Enteral (e.g., via GI tract) - Oral, rectalParenteral - Intravenous, intramuscular, subcutaneousTransdermal (topical)Mucosal - sublingual, intranasal, ocular, intravaginalInhalationIntrathecal (spinal fluid)IntraarticularIntraosseousIntraperitonealIntraocular
Routes of Drug Administration
Slide6Time to Effect vs Route
Intravenous 30-60 secIntraosseous 30-60 secEndotracheal 2-3 minInhalation 2-3 minSublingual 3-5 minIntramuscular 10-20 minSubcutaneous 15-30 minRectal 5-30 minOral 30-90 minTransdermal min to hours
Best for emergencies
Routes of Drug Administration
Slide7Routes of Drug Administration
Route
Main Advantages
Main Disadvantages
Oral
Easy, inexpensive, safe,
preferred by patients,
Slow time to effect,
conscious
ness required,
requires functional gut,
bioavailability can be limited
Rectal
Easy,
good absorption,
no first pass metabolism,
good for infants/children
Not preferred by patients
Intravenous
Rapid onset, dependable,
100% bioavailability
Requires an I.V. cannula,
expensive, labor intensive,
pain, risk of infection, bleeding
Intramuscular/
Subcutaneous
Relatively fast onset, no first pass metabolism
Absorption can be unpredictable,
pain, risk of bruising/bleeding
Slide8Routes of Drug Administration
RouteMain AdvantagesMain DisadvantagesTransdermalEasy, non-invasive,high patient satisfactionSlow time to effect, most drugs not absorbed through skinInhalationRapid absorption, limited systemic deliveryEffectiveness depends on patient technique
Choice of route depends on clinical urgency, type and properties of drug
including bioavailability, condition of patient including age and mental status,
and patient preference
Slide9Oral Drug Administration
Pharmaceutical phase of absorption
Slide10Oral Drug Administration
Factors affecting oral absorption
Intrinsic physical and chemical properties
Bioavailability
Gastric acidity and digestive enzymes
Gastric emptying time
Relationship to food intake
Drug metabolism by intestinal epithelium (CYP3A4)
Drug efflux from intestinal epithelial cells (p-glycoprotein)
Inhibitors of CYP3A4 and drug transporters
Slide11Across the Stomach
Across the Small Intestine
Ibuprofen in the Stomach versus Small Intestine
Slide12The uncharged form of ibuprofen in the stomach is near 100% whereas it is about 1% in the intestineThe surface area of the intestines is several thousand times larger than that of the stomachLarge surface area of the small Intestines accounts for increased drug absorptionLonger transit times: <1 hr in the stomach and >3 hr in the small intestine also contributes.These factors explain why ibuprofen is largely absorbed from the intestine.
Ibuprofen Absorption in the Stomach
vs Small Intestine
Slide13Bioavailability
Bioavailability refers to the fraction of an administered doseof unchanged drug that reaches the systemic circulation.
Metabolism in either the intestinal wall or liver before the drug
can reach the systemic circulation reduces bioavailability
Slide14Bioavailability
Bioavailability refers to the fraction of an administered dose
of unchanged drug that reaches the systemic circulation.
Metabolism in either the intestinal wall or liver before the drugcan reach the systemic circulation
Slide15First Pass Metabolism
Slide16Bioavailability
Bioavailability refers to the fraction of an administered doseof unchanged drug that reaches the systemic circulation.
Examples of Drugs with
HIGH
bioavailability
Acetaminophen
Amoxicillin
Codeine
Diazepam
Metronidazole
Trimethoprim
warfarin
Slide17Bioavailability
Bioavailability refers to the fraction of an administered doseof unchanged drug that reaches the systemic circulation.
Examples of Drugs with
LOW
bioavailability due to
first pass metabolism
Morphine*
Demerol*
Lidocaine*
Nitroglycerin*
Propranolol
*not administered orally
Slide18Bioavailability
Bioavailability refers to the fraction of an administered doseof unchanged drug that reaches the systemic circulation.
Features of a chemical compound that make it a likely orally active drug in humans
Lipinski's rule of five:
No more than
5
hydrogen bond donors (the total number of nitrogen–hydrogen and oxygen–hydrogen bonds)
No more than
10
hydrogen bond acceptors (all nitrogen or oxygen atoms)
A molecular mass less than
500
daltons
An octanol-water partition coefficient log
P
not greater than
5
Slide1980 year old man was hospitalized in Miami Florida after 4 days of generalized muscle pain, fever, dark urine and fatigue. He was on his annual winter vacation in Miami and was feeling well until this illness.Medical history – hypercholesterolemia, stably treated with atorvastatinTemperature – 100, Blood pressure – 170/110, Pulse – 90Muscle tenderness in thighs, upper armsUrine – 4+ hemoglobin, Serum creatinine 4.2 mg/dlCPK – 19,000 (normal level < 100)
Diagnosis:
nontraumatic
rhabdomyolysis with acute kidney injury, possibly secondary to statin therapy
Slide2080 year old man was hospitalized in Miami Florida after 4 days of generalized muscle pain, fever, dark urine and fatigue. He was on his annual winter vacation in Miami and was feeling well until this illness.Medical history – hypercholesterolemia, stably treated with atorvastatinTemperature – 100, Blood pressure – 170/110, Pulse – 90Muscle tenderness in thighs, upper armsUrine – 4+ hemoglobin, Serum creatinine 4.2 mg/dlCPK – 19,000 (normal level < 100)
Diagnosis:
nontraumatic
rhabdomyolysis with acute kidney injury, possibly secondary to statin therapy
Slide2180 year old man was hospitalized in Miami Florida after 4 days of generalized muscle pain, fever, dark urine and fatigue. He was on his annual winter vacation in Miami and was feeling well until this illness.Dietary history revealed he had been drinking 8 ounces of freshly squeezed grapefruit juice every morning when taking his medication (atorvastatin).
Chemicals found in grapefruit juice inhibit CYP3A4 and p-glycoprotein
Increases bioavailability of certain medications
May cause toxic elevations of plasma drug concentrations
Slide22First Pass Metabolism
Slide23Effect of Grapefruit Juice on Drug
Oral Bioavailability
The magnitude of grapefruit juice effect is related to the inherent oral bioavailability of the drug.
Large effects occur
with low bioavailable
drugs
Slide24Bioequivalence
Bioequivalence refers to drug preparations that exhibit the same bioavailability and pharmacokinetics.
Generic drugs need to meet 3 criteria:
Pharmaceutical equivalenceBioequivalenceEffective and safe
Pharmaceutical equivalence refers to different drug preparations with same active ingredient, concentration, dose, route of administration- Does NOT equate to bioequivalence!
A generic drug must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the original drug.
Slide25Bioequivalence
Bioequivalence refers to drug preparations that exhibit the same bioavailability and pharmacokinetics.
Example of
bioequivalent
generic drug
Slide26Bioequivalence
Bioequivalence refers to drug preparations that exhibit the same bioavailability and pharmacokinetics.
Example of
non-bioequivalent generic drug
Original
Generic
Slide27Drug Distribution
The reversible transfer of a drug between the systemic circulation (blood) and extra-vascular (interstitial) fluids and tissues.
Absorption
Elimination
Distribution
Slide28Drug Distribution to Tissues
Perfusion-limited tissue distribution
- Initial rate of drug distribution to various sites depends on blood flow to the tissue. First phase: Rapid distribution to organs of high blood flow: brain, heart, liver, and kidneysSecond phase: Slower drug delivery to muscle, most organs, skin and fat which have moderate blood flowPermeability-limited tissue distributionCertain compartments have restricted access Central nervous system (blood-brain barrier) Placenta
Slide29Drug Distribution to Tissues
Affinity of the drug for tissue site
Lipid soluble,
nonionized
drugs are readily distributed to all organs - particularly adipose tissue.
Ionized drugs in general will remain in the plasma and interstitial compartments
Tissue distribution affects the
apparent volume of distribution
, which in turn affects the half-life of drugs in the body.
Slide30Apparent Volume of Distribution
A hypothetical volume needed to contain the total amount of administered drug at the same concentration as observed in plasma.
V
D
=
Total amount of drug administered
Plasma concentration
The minimum VD for any drug is ~3L, equivalent to the plasma volume in an adult.
Many drugs can accumulate in tissues, leading to very high V
D
values.
Slide31Apparent Volume of Distribution
DrugVD (L)*Amoxicillin15Erythromycin55Ethanol49Diazepam77Morphine230Fluoxetine2,500Chloroquine13,000
* per 70 kg body weight
Slide32Drug Binding to Plasma Proteins
Many drugs are bound to proteins in the blood
Albumin
binds drugs that are
weak acids
Alpha-acid glycoprotein
binds drugs that are
weak bases
Slide33Drug Binding to Plasma Proteins
Many drugs are bound to proteins in the blood
Protein-bound drugs are pharmacologically inactive
Protein binding lowers the effective concentration
greater binding = less available free active drug
Protein binding slows distribution to extravascular sites
greater binding = less metabolized and eliminated,
resulting in longer half-life
Reversible binding may serve as a storage depot to prolong action
Slide34Drug Binding to Plasma Proteins
Diseases may affect protein binding of drugs
hypoalbuminemia
(liver failure, malnutrition, kidney diseases with proteinuria) can affect free drug concentration without affecting total plasma concentration.
Drugs may compete for protein binding and cause drug displacement
Example
: sodium valproate can displace phenytoin from albumin and increase free phenytoin concentration
Measurement of free drug concentrations is important
especially when the drug has low therapeutic index!
Slide35Drug Binding to Plasma Proteins
Effect of low plasma albumin on free phenytoin levels
Slide36Drug Distribution to Central Nervous System
CNS is less accessible to drugs despite high blood flowLipid-soluble drugs are most permeable to CNSBlood-brain barrier (BBB)Blood – cerebrospinal fluid (CSF) interface
Slide37Drug Distribution to Central Nervous System
Blood-brain barrier
Anatomic barrier
L
ack fenestration, and vesicles in endothelial cellsTight junctions Limited extracellular spacecovered by basal membrane, astrocyte end-foot processes and pericytes.
Brain capillary endothelial cells:
Slide38Drug Distribution to Central Nervous System
Blood-brain barrier
Functional
barrier
EffluxTransporters
Slide39Effect of p-glycoprotein on CNS drug penetration
WT
Ratio
Wild-type (WT)
p-
gp
knockout (KO)
Sprachlin
et al 2005, Drug
Metab
Dispos
33:
165-174
Slide40Effect of p-glycoprotein on CNS drug penetration
Sprachlin et al 2005, Drug Metab Dispos 33: 165-174
Quinidine is ‘pumped out’ of the CNS by p-gp, whereas ritonavir is not.
WT
Ratio
WT
Ratio
Wild-type (WT)
p-
gp
knockout (KO)
Slide41Increased drug delivery to the CNS byp-glycoprotein inhibition
Sadeque
et al., 2000, Clin Pharmacol Ther. 68: 231-237
Respiratory depression due to loperamide occurs at the same plasma concentration (60 min) when quinidine is co-administered.
Slide42Blood-Cerebrospinal Fluid Interface
Slide43Blood-Cerebrospinal Fluid Interface
A barrier to drug distribution resides in the epithelial cells of choroid plexus, which have tight junctions
Not as restrictive as BBB
Lipid-soluble drugs can penetrate CSF
Choroid plexus capillaries are
fenestrated
The epithelial cells
lining brain ventricles (ependymal cells)
are
leaky and allow
paracellular
transport.
Intrathecal drug delivery of certain drugs successfully bypasses the BBB.