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Eastern University – Nicanor Reyes Medical Foundation PHASE II

PHARMA A: PHARMACOKINETICS - 20 – 300 subjects; patients WITH DISEASE
Dr. Abraham Cruz, MD - Evaluate
o Efficacy – does it work?
By the end of this lecture, the learner should be able to: o Safety
- Describe the different phases of drug development - Reasons for dropping
- Describe the physicochemical and physiologic factors that o Less effective than anticipated
affect absorption, distribution, metabolism, and excretion o Too toxic, unacceptable adverse effect
- Explain how dose, bioavailability, rate of absorption, volume o Low benefit-t0-risk ratio
of distribution, clearance, and half-life affect plasma o No more effective than other available drugs
concentrations after drug administration.
- Compute and adjust dosage regimens in relation to changes in PHASE III
volume of distribution and clearance. - Randomized, controlled multicenter trials
- Double blind
2 DISCIPLINES OF PHARMACOLOGY - Large patient groups (300 – 3000)
- Pharmacokinetics – drug disposition and the way the body - Patients WITH DISEASE
affects the drug with time (i.e., factors that determine its - Usually compared with “gold standard” and placebo
absorption, distribution, metabolism, and excretion); - Most expensive, time consuming, difficult trials to design and
BIOLOGIC FATE OF DRUGS run
- Pharmacodynamics – effect of the drug on the body
PHASE IV
DRUG DEVELOPMENT AND EVALUATION - Post marketing surveillance
- Possible therapeutic value à drug development - Pharmacovigilance
- DOH-BFAD à FDA - Detect any rare or long term adverse effects
o Ensure safety and reliability - Report any untoward or unexpected adverse effect not seen
o Must undergo pre-clinical trials and clinical trials (phase during
I, II, III, IV) - pre-clinical and phases I – III
o After prolonged use and wide distribution
o Risk of malignancy
o Thrombotic events
o Idiosyncratic side effects in special populations

DRUGS WITHDRAWN FROM THE MARKET
- Troglitazone (Rezulin) – liver failure
- Rofecoxib (Vioxx) – thrombotic events
- Dexfenfluramine (Redux)– cardiotoxicity

COMPLIANCE
- extent to which patients follow treatment instructions
PRE-CLINICAL TRIALS - 4 types of NON-COMPLIANCE
- In vitro and animal studies o Failure to obtain medication – no prescription, discharge
- Purpose meds, financial
o Evaluate toxicity o Failure to take the medication as prescribed – due to
o Determine presumed effects inadequatecommunication
- Reasons for dropping o Patient prematurely discontinues medication – usually
o Lack therapeutic activity due to symptomatic relief
o Toxic to living animals o Patient (or another person) takes the medication
o Teratogenic (adverse effect on fetus) inappropriately
o Small or narrow margin of safety - Patient issues
o must be taken at regular intervals and for a certain
PHASE I duration to be effective
- 20-50 HEALTHY volunteers (young men) o Some forms require inpatient treatment à issues:
- Clinical investigators evaluate: transport, work, having young children
o Safety (adverse effects) - More problematic in pediatrics
o Pharmacokinetics o Parent/guardian: give medication and follow directions
o Therapeutic effects (?) o Child: cooperate with guardian
- Reasons for dropping - Practical dosage forms à ease of administration à achieve
o Lack therapeutic effect compliance
o Unacceptable adverse effects o Sugar-coated tablets
o Highly teratogenic o Elixirs and suspensions for children (different colors and
o Too toxic flavors)
- Route of administration – may affect compliance;

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 o e.g. oral à simpler than parenteral § Protonated form of a weak acid (HA)
- Dosing schedule à easier to follow, less frequent § Unprotonated form of a weak base (B)
administration àincreased compliance o Henderson-Hasselbalch trapping – occurs when a
weakly acidic or basic drug equilibrates across a
Strategies to Improve Compliance membrane separating regions of different pH
- Enhanced communication
- Assessment of personal, social, and economic conditions HENDERSON-HASSELBALCH EQUATION
- Development of routine
- Systems to assist taking of medications (containers, alarms)
- Mailing of refill reminders
- Instruction about how to understand and monitor effects of
medication
- Active patient participation REMEMBER:
- neutral à uncharged/unionized/non-polar àmore lipid
PHARMACOKINETICS soluble
- drug should reach its site of action; scenarios: - law of mass action à reactions move to the:
o Drug is active, lipid soluble, stable à given as such o left in an acid environment (low pH, excess protons
o Prodrug à absorbed and distributed à converted to available)
the active drug by metabolic processes o right in an alkaline environment
o Apply drug directly to target tissue o the lower the pH relative to the pKa , the greater will
- most common scenario: administer drug in one compartment be the fraction of drug in the protonated form
à move to site of action in another compartment; requires:
o Permeation
§ Absorption
§ Distribution
o Elimination
§ Metabolic inactivation/activation
§ Excretion

MOVEMENT OF DRUGS IN THE BODY
- Drugs must cross barriers (intestinal wall, blood-brain barrier)
to be absorbed or distributed; via passive diffusion,
facilitated diffusion, or active transport
- PASSIVE DIFFUSION – no energy required; no carrier, not
saturable; proportional to concentration gradient
o for very small molecules (lithium, alcohols, gases)
o requires some degree of lipid solubility if across lipid
membranes
FICK’S LAW OF DIFFUSION

- For a weak base such as hypothetical drug shown (pKa – 7.4),
the region with lower pH (greater proton concentration) will
trap more drug because the protonated form is less soluble
and cannot diffuse back across the membrane
Where: - the Henderson-Hasselbalch equation predicts that if the total
- C1 = higher concentration concentration of this weak base in the blood at pH 7.4 is
- C2 = lower concentration 2mg/L (50% neutral, 50% protonated), the equilibrium
- Area = cross-sectional area of the diffusion path concentration in the urine at pH 5.4 will be 100 mg/L (1 mg/L
- Permeability coefficient = measure of the mobility of the unprotonated, 99 mg/l protonated)
drug molecules in the medium of the diffusion path - Ionized form of the drug will be trapped in the renal tubules
- thickness = length of the diffusion path and thus excreted in the urine
- lipid diffusion
o lipid: aqueous partition coefficient - major HENDERSON-HASSELBALCH TRAPPING
determinant of drug mobility - Used in detoxification of overdosed patients à accelerate
excretion by:
MOVEMENT OF DRUGS IN THE BODY: o Acidifying (NH4Cl; high-dose vitamin C ) if the patient
+
PASSIVE DIFFUSION used a weak base (BH );
- Lipid solubility – partly determined by the electrical charge § ex. Amphetamines
(structure) o Alkalinizing (NaHCO3; acetazolamide) if the patient took
-
- Weak acids and bases – determined by the pH of the medium a weak acid (A );
according to the Henderson-Hasselbalch equation § ex. Aspirin, barbiturates
o Uncharged, more lipid-soluble form

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 MOVEMENTS OF DRUGS IN THE BODY - The higher the lipid/water p.c. the greater the rate of transfer
- FACILITATED DIFFUSION – no energy required; carrier across the membrane
required; saturable
- ACTIVE TRANSPORT – against concentration / electrical
gradient; requires energy; requires carrier; saturable
o By carriers – structurally related to endogenous
molecules (amino acids, sugars)
o Endocytosis –very large or very polar (vitamin B12, iron)
à complexed with proteins and actively transported
into cells
- Other factors:
o Drug solubility, drug concentration, drug ionization,
surface area,vascularity

DRUG ABSORPTION
- Site of administration à circulation
o Drugs may be administered directly at their site of
action or may be absorbed into the circulation to be
distributed to distant sites (review routes of
administration above)
- Will be affected by both chemical and physiological factors,
since the drugs must cross barriers in order to enter cells or to SIZE
transfer between body compartments - Small size = ↑ absorption
- Most drugs are small molecules (molecular weight <1000) à
BIOAVAILABILITY can diffuse across membranes in their uncharged state
- Considers both absorption and metabolism
- (F) - fraction of the plasma concentration of a drug for any pH
given route of administration compared with the IV route; the - Most drugs are weak bases, weak acids, or amphoteric
fraction of (active) drug that reaches the systemic - Important determinants of drug fraction in the unionized
circulation/site of action after administration by any route form:
- AUC (area under the plasma-concentration curve) quantitates o pH of the environment in which drugs dissolve
drug absorption into systemic circulation o pKa value of the drug
§ pH at which 50% of the molecules are in the
F = AUCroute (extravascular) /AUCIV (intravascular) ionized form; characterized by the Henderson-
Hasselbalch equation
- proportion of the drug that passes into systemic circulation
- 100% (1) after IV injection; variable for oral administration (or REMEMBER THE:
any other route for that matter); depends on: HENDERSON-HASSELBALCH EQUATION
o Drug
o Individual
o Circumstances under which the drug is given
- Bioequivalence – comparison of two formulations of the same
compound; have the same bioavailability and same rate of
absorption REMEMBER:
- neutral à uncharged/unionized/non-polar àmore lipid
Cell Membranes soluble
- lipid bilayers à - law of mass action à reactions move to the:
absorption is usually o left in an acid environment (low pH, excess protons
proportional to the lipid available)
solubility of the drug o right in an alkaline environment
- Un-ionized molecules (B) o the lower the pH relative to the pKa , the greater will
- more lipid soluble be the fraction of drug in the protonated form
-
+
Ionized (BH ) - surrounded by
a “shell” of water
+ +
- B + H ↔ BH


LIPID-WATER PARTITION COEFFICIENT
- ratio of the concentration of the drug in two immiscible
phases: a nonpolar liquid or organic solvent (representing
the membrane); and an aqueous buffer, pH 7.4
(representing the plasma)

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 CASE:
- A 12 year old child has bacterial pharyngitis and is to
receive an oral antibiotic. Ampicillin is a weak organic acid
with a pKa of 2.5. What percentage of a given dose will be
in the lipid soluble form in the duodenum at a pH of 4.5?
o A. about 1%
o B. about 10%
o C. about 50%
o D. about 90%
o E. about 99%
EXPLANATION:
Basic equation: Ampicillin is an acid, so it is more ionized in an alkaline pH and
Log (protonated form/unprotonated form) = pKa - pH less ionized in an acidic pH. The Henderson-Hasselbalch equation
+
- for acidic molecules: HA ↔ H + A predicts that the ratio changes from 50/50 at the pH equal to the
pKa = pH + log ([HA]/[A]) pKa, to 1/10 (protonated/unprotonated) at 1 pH unit more
+ +
- for basic molecules: BH ↔ B + H alkaline than the pKa, and 1/100 at 2 pH units more alkaline. For
+
pKa = pH + log ([BH ]/[B]) acids, the protonated form is the non-ionized, more lipid-soluble
- drugs will tend to exist in the ionized form when exposed to an form
environment with a pH opposite to their own state, i.e. acids
become more ionized with increasing pH (basic medium) COMPUTATION
- log (protonated/unprotonated) = pKa - pH
ION TRAPPING - substituting the values, we get log (protonated/unprotonated)
- Body fluids where a pH difference from blood pH will favor = 2.5 - 4.5
trapping or reabsorption: - log (protonated/unprotonated) = -2
o stomach contents - to get the actual value of (protonated/unprotonated), you
o small intestine need a scientific calculator and get the antilog of -2
o breast milk - if u remember a little bit of calculus, the antilog of -2 is also
o aqueous humor (eye) equal to 10 raised to the exponent of -2
o vaginal secretions - 10 raised to the exponent of -2 is equal to .01
o prostatic secretions - • .01 = 1/100 = 1%

pH ROUTES OF ADMINISTRATION
- 3 important body compartments in relation to drugs: - Topical – drug is placed where it is needed; no need to cross
o plasma: pH = 7.4 membranes
o stomach: pH = 2 o Examples: skin ointments; ear, nose, or eye drops;
o urine: pH = 8 aerosols inhaled in asthma management
- Examples and Implications o Note:
o Aspirin – weak acid (pKa = 3.5); absorption is favored in § antacids – elicit their effect in the stomach;
the stomach (uncharged); may damage stomach in classified as topical
high doses o Some references classify the topical route as a
o Morphine – weak base (pKa = 8); highly charged in the parenteral route
stomach, quite charged in the plasma, and half- - Enteral – drug reaches its target via the gut
charged in the urine o Least predictable ROA due to:
§ Can cross BBB, but poorly and erratically § Liver metabolism
absorbed from the stomach and intestines, and § Chemical breakdown
metabolized by the liver à must be given by § Possible binding to food
injection or delayed- release capsules o Drugs must cross several barriers
§ May or may not be a problem depending on
Weak Bases physicochemical properties (charge, size)
- Quaternary ammonium o HOWEVER, most drugs are administered ORALLY
compounds (e.g. (because of convenience) unless the drug is:
succinylcholine, § Unstable or rapidly inactivated in the
tubocurarine) gastrointestinal tract
- always charged (polar) à § Absorption from the gastrointestinal tract is
can not cross membranes uncertain due to:
(remains in one • Metabolism by the liver or intestines
compartment); must be • Vomiting
injected if systemic effect is • A disease that may affect drug absorption
desired) o Disadvantage of oral route: absorption is slower and less
complete than with other routes
o Buccal or sublingual route
§ Avoids portal circulation à valuable when drug

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 is subject to a high degree of first-pass - inhalation 2-3 minutes
metabolism (unavoidable if taken orally) - sublingual 3-5 minutes
§ For potent drugs with agreeable taste (e.g. - intramuscular 10-20 minutes
sublingual nitroglycerin to relieve acute angina - subcutaneous 15-30 minutes
attack) - rectal 5-30 minutes
o Rectal route (suppositories) - ingestion 30-90 minutes
§ Less first-pass metabolism by the liver because - transdermal (topical) variable (minutes to hours)
venous return from the lower GIT is less
compared to that from the upper GIT The ROA is determined by the physical characteristics of the
§ Disadvantage: inconsistent absorption drug, the speed which the drug is absorbed and/ or released, as
- Parenteral Routes well as the need to bypass hepatic metabolism and achieve high
o Intravascular (IV, IA)- placing a drug directly into the concentration at particular sites.
blood stream
o Intramuscular (IM) - drug injected into skeletal muscle No single method of drug administration is ideal for all drugs in all
o Subcutaneous - Absorption of drugs from the circumstances.
subcutaneous tissues
o Inhalation (?)- Absorption through the lungs DRUG DISTRIBUTION
- Parenteral – drug administration that avoids the gut - Circulation à tissue binding sites
o Example: insulin – protein drug; stomach acidity and o small molecular size à leave circulation by capillary
digestive enzymes destroy the drug filtration àtissues
§ SQ or IV (depends on preparation) o Can influence onset, intensity, and duration of action
o Intravenous injection - Half-life (t½) – can be affected by distribution (2-compartment
§ Advantages: model), although mainly affected by elimination
• Most direct route à enters the - Rate and extent depend on:
bloodstream directly; bypasses o Blood flow to the tissue
absorption o Size of the organ
• Drug is distributed in a large volume o Binding
and/or acts rapidly o Apparent volume of distribution
o Important for drugs that must be given continuously by o Lipid solubility
infusion or for drugs that damage tissues
BLOOD FLOW TO THE TISSUE
- High blood flow (viscera, brain, muscle) – receive significant
amounts of drug in a short time
- Low perfusion (fat, bone) – receive drug more slowly

SIZE OF THE ORGAN
- Large organs (e.g. skeletal muscle) – take up large quantities
of the drug if allowed to reach steady state

PERFUSION RATE
- Considers organ size AND blood flow
o Alternative parenteral routes - Volume of blood that flows per unit time per unit volume of
§ Subcutaneous the tissue (ml/min/ml)
§ Intramuscular - Permeability-limited vs perfusion-limited distribution
§ Epidural or intrathecal injections
§ Transdermal patches – slowly released; used for
prolonged action
o Rate of drug absorption from the site on injection can be
decreased by:
§ Binding the drug to a vehicle
§ Co-administering a vasoconstrictor (usually
epinephrine) to reduce blood flow to the site
Special formulations – modify rate of absorption
- IM injection of drugs dissolved in oil à slow absorption; - Permeability-rate limited when:
repository form o Drug is ionic/polar/water soluble
- Oral intake of drugs encapsulated in slowly dissolving shells o The highly selective physiologic barriers restrict the
(liposomses)à slow, continuous absorption diffusion of drugs to the inside of the cell
- Perfusion-rate limited when:
Time until effect o Drug is highly lipophilic
- intravenous 30-60 seconds o Membrane is highly permeable
- intraosseous 30-60 seconds Some Applications:
- endotracheal 2-3 minutes - Highly lipophilic drugs can cross most selective barrier like

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 BBB; Ex. Thiopental factor which is normally excreted by kidney
- Highly permeable capillary wall permits passage of almost - Determinants of alpha1-acid glycoprotein level
all drugs (except those o may increase in response to: surgery, chronic pain,
- bound to plasma protein) acute MI
- Highly perfused tissues Lungs, Kidneys, Liver, Heart, Brain - Alpha1-acid glycoprotein levels are low in neonates
are rapidly equlibriated with lipid soluble drugs o Decreased protein binding of diazepam, propanolol,
- Drug distribution in a particular tissue or organ depends sufentanil, lidocaine
upon the size of tissue (Volume) & Tissue/blood partition - May possibly increase the risk of toxicity because the plasma
coefficient concentration of the active drug has been increased, yet
- Ex.Thiopental i.v (liphopillic drug) & high tissue/blood depending on the drug à increase in free fraction may
partition coefficient towards actually increase its metabolism because more drug is
- brain & adipose tissue available to metabolizing enzymes
- The brain is highly perfused organ à drug is distributed o Example: aspirin can displace diazepam from albumin
fast and shows rapid onset of action on the CNS than
poorly perfused adipose tissue PERMEATION, BLOOD FLOW, AND PROTEIN BINDING
- Perfusion-Rate Limitation
BINDING o Membrane offers no resistance
- Bulk transfer in the blood à very fast (instantaneous) o Drug in the blood leaving the tissue is in equilibrium
- Drugs exist either dissolved in blood or bound to plasma with that of the tissue à blood and tissue viewed as
proteins one à equilibrium achieved instantaneously
- Plasma proteins: o Alteration in protein content is NOT expected to affect
o Albumin – most important circulating protein for rate of transport at a given concentration
binding many acidic drugs - Permeability-Rate Limitation
o Globulin/α1-glycoprotein – bind basic drugs; increases o Membrane resistance to drug movement is high
with age o Movement is slow and insensitive to changes in
- Bound drug - confined to the vascular system is unable to perfusion à equilibrium is not achieved by the time
exert its actions the blood leaves tissue à view blood and tissue as
o Becomes a problem if more than 80% of the drug is separate
bound o Altered protein-binding influences rate of transport by
o Drug interaction: one drug may displace another à free affecting unbound concentration
fraction of one drug may increase
- Importance: Only free (i.e. unbound) fraction is able to cross APPARENT VOLUME OF DISTRIBUTION (Vd)
cell membrane - calculated pharmacokinetic space into which a drug is
- When protein binding is high distributed; the apparent volume in the body available to
o Drugs kept in plasma contain the drug; NOT a physiologic value; not absolute for
o Plasma concentration is high any given drug
o Calculated Vd is lower
- Only unbound fraction can enter hepatocytes and cross Vd = dose administered (or amount of drug in the body) /
Glomerulus initial apparent plasma concentration
o undergo hepatic metabolism and glomerular filtration
- Changes in protein binding VOLUME DISTRIBUTION
o Especially important for drugs which are: highly protein-
bound, with narrow therapeutic index, distributed
primarily in the plasma
§ Small changes in binding à Large changes in free
fraction
§ e.g. propanolol, phenytoin, diazepam
- General determinants of protein binding APPARENT VOLUME OF DISTRIBUTION (Vd)
o Lipid solubility à parallels protein-binding - Vd values that amount to less than a certain body
o Plasma concentration of the drug compartment volume indicate that the drug is contained
§ Low plasma concentration is more likely to be within that compartment; examples
highly protein bound o < 3 L = plasma
o Number of available binding sites (plasma protein) o < 5 L = vasculature/blood
- Plasma albumin binding is non-selective à drugs can compete o < 15 L = extracellular fluid
with each other o > 15 L = total body water (TBW); 42 L [average 70 kg
o Ex. Sulfonamides can displace unconjugated bilirubin man x 60%; for women, 50% of body weight in kg is
from albumin à bilirubin encephalopathy in neonates body water due to lower lean muscle mass and higher
(kernicterus) fat content (adipose tissue)]
- Protein binding and renal failure - Some important volumes and proportions
o Protein-bound fraction of a drug decreases (despite o Intracellular volume (ICV) = 2/3 of TBW
normal plasma protein level); possible causes: o Extracellular volume (ECV) = 1/3 of TBW
alteration of protein, displacement by a metabolic o Interstitial volume = 2/3 of ECV

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 o Plasma volume = 1/3 of ECV PHARMACOGENOMICS:
- Some drugs (usually basic) have a volume of distribution that
exceeds body weight à (+) tissue binding à these drugs tend
to be contained outside the circulation and may accumulate
in certain tissues:
o Lead – bone
o Quinacrine – nucleic acids; concentrates in the liver 200
times more than in the plasma

LIPID SOLUBILITY
- Very lipid-soluble substances (e.g. thiopental) – adipose tissue
and brain
o Reach higher concentrations in tissues with high fat
content
o Half-life will be much longer in obese patients*
- *Plasma half-life is generally directly proportional to a drug’s
duration of action, but not always.

Some Applications – Sedative Hypnotics
Absorption and Distribution
- Most are lipid-soluble and are absorbed well from the GIT
with good distribution to the CNS
- highest lipid solubility (eg. Thiopental) enter the CNS
rapidly à determine
- onset of action àuse as induction agents in anesthesia
o CNS effects are terminated by rapid redistribution
from the brain to other highly perfused tissues
- Other drugs with rapid onset of action – eszopiclone,
zaleplon, zolpidem FIRST-PASS METABOLISM
- Especially relevant for orally administered drugs
Benzodiazepine Chemistry and Lipid Solubility - Intestinal absorption à portal circulation (portal vein) à liver
- Variations in lipid solubility and pKa affect whether or not metabolism àless drug reaches systemic circulation à ↓
they are quickly absorbed bioavailability
- and effective shortly after administration (ONSET) - Implications:
- List of some BZDs and their pKa o Higher doses of drug must be given
• Bromazepam - 11.0 o Individual variation à drug effects can be unpredictable
• Clonazepam - 10.5 (1-position);1.5 (4- position) - If it occurs to a high degree (lidocaine, nitroglycerin) à give by
• Diazepam - 3.3 another route
• Flunitrazepam -1.8
• Flurazepam - 8.2
• Lorazepam - 11.5
• Medazepam - 6.2
• Nitrazepam - 10.8
• Oxazepam - 1.8
• Prazepam - 3.0

DRUG METABOLISM
- Most drugs are metabolized prior to excretion
- A small number of drugs are fully ionized at physiologic pH
(7.4) à highly polar à metabolized only to a minor extent, if
at all à excreted unchanged
- Sequential metabolic reactions: phase 1 and 2 - Magnitude of first pass hepatic effect: Extraction ratio (ER)
- Liver – major site; other sites: ER = CL liver / Q
o Kidneys, lungs, gastrointestinal tract where Q is hepatic blood flow (usually about 90 L per hour)
- Systemic drug bioavailability (F) may be determined from
the extent of absorption (f) and the extraction ratio (ER):
F = f x (1 -ER)

PHASE 1 METABOLIC REACTIONS
- Oxidation, reduction, hydrolysis
- Make the drug more reactive and capable of combining with
polar conjugating groups

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 o ↑ water solubility à ↑elimination OTHER PHASE 1 METABOLIC REACTIONS
- Introduce a functional group (-OH, -NH2, -SH, or COOH): REDUCTION - involve microsomal enzymes; less
o increases polarity of the drug molecule common than oxidation reactions
o provides a site for phase 2 reactions - Examples:
- Drug activity may or may not change à potentially dangerous • Prednisone (prodrug) – reduced to the
- Activity decreases with age active glucocorticoid prednisolone
• Warfarin (anticoagulant) – inactivated
OXIDATION by the transformation of a ketone
- Loss of electron or gain of group to a hydroxyl group
oxygen HYDROLYSIS - Not restricted to the liver
- most common and - Example: aspirin à spontaneously
important hydrolyzed to salicylic acid in moisture
- catalyzed by the
microsomal mixed function PHASE 2 METABOLIC REACTIONS
oxidase system - Drugs with a suitable site
o located on the SER - (present before phase 1 or
o consists of a number result of a phase 1 reaction)
of enzymes known as cytochromes P450 (CYP à susceptible to phase 2
enzymes/CYT P450) reactions
- CYP enzymes: most important of the phase 1 enzymes o Conjugation – the
o Found in the SERs mainly in hepatocytes, and in the GIT, attachment of a large
kidney, and lungs chemical (polar) group
o require oxygen, reduced nicotinamide adenine to a functional group
dinucleotide à ↑ hydrophilicity à
o phosphate (NADPH), and NADPH cytochrome P450 easily excreted
reductase § Main: liver, and
o over 50 isoforms in humans – constitutive or inducible in other tissues
response to certain signals
§ Substrate specificities tend to be low and can
overlap à many drugs can be oxidized by one Chemical Groups Involved
or more isoforms - Glucuronic acid
- Sulphate
Major human P450 families involved in phase 1 metabolism - Methyl and acetyl groups
- CYP1A2 (caffeine ciprofloxacin, theophylline, R-warfarin) - Glutathione
- CYP2C9 (ibuprofen, naproxen, phenytoin, S-warfarin) - Amides
- CYP2D6 (codeine, dextromethorphan, fluoxetine,
haloperidol, loratadine, metoprolol, paroxetine, PHASE 2 METABOLIC REACTIONS
risperidone, thioridazine, venlafaxine), - Conjugating enzymes
- CYP2E1 (ethanol, INH, acetaminophen [at high doses]) exist in many isoforms,
and show relative
- CYP3A4 (responsible for metabolism of the largest substrate and
proportion of drugs [50 – 60%]; alprazolam, metabolite specificity
carbamazepine, cyclosporine, diltiazem, erythromycin, - Conjugates are almost
fluconazole, itraconazole, ketoconazole, lidocaine, invariably inactive
lovastatin, midazolam, nifedipine, quinidine, simvastatin, o Important
tacrolimus, verapamil) exception:
morphine à morphine-6-glucuronide (analgesic effect
OXIDATION lasts longer than parent molecule)
- Usually result in drug
inactivation FACTORS AFFECTING METABOLISM
- sometimes produce ENZYME INDUCTION
a pharmacologically - increased synthesis or decreased degradation of enzymes;
active metabolite à occurs as a result of the presence of an exogenous substance
duration of action - Some drugs can increase the activity of certain CYP isoforms
may exceed the àincrease their own metabolism as well as that of other
original drug drugs
(prodrug) o Ex. Phenobarbital, rifampin, phenytoin, carbamazepine,
St. John’s wort, chronic ethanol consumption

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 - Smoking - increases metabolism of certain drugs because of
CYP1A2 induction by nicotine

ENZYME INHIBITION
- two drugs competing for a metabolic enzyme à decreased
metabolism of one or both
- Grapefruit juice – potent inhibitor of CYP3A4
- Other drugs: erythromycin, ketoconazole, ciprofloxacin,
quinidine, cimetidine, omeprazole, ritonavir,
chloramphenicol, acute alcohol intoxication

DIET
- *Diet may also affect drug
metabolizing enzymes –
ratio of protein and
carbohydrate, flavonoids
in vegetables, polycyclic
aromatic hydrocarbons in
barbecued foods

Acetaminophen Poisoning
- example of a drug that can be lethal at high doses (203
times the maximum therapeutic dose) due to accumulation
of metabolites
- conjugated with glucuronic acid and sulphate in phase 2
metabolic process
o saturation occurs in high doses à metabolism by
mixed function oxidases occurs à forms the toxic
metabolite N-acetyl-p-benzoquinone (NAP1I;
metabolized by glutathione) à glutathione depletion
à NAPQI binds to nucleophilic constituents of the
cell à liver and kidney necrosis
o N-Acetyl or methionine: used as antidote
o Increases liver glutathione formation and conjugation
reactions, respectively

DRUG EXCRETION
- Occurs in a variety of ways
- Kidneys (urine), GIT (bile and feces), lungs (exhaled air),
breastmilk, sweat
- Clearance rate = volume of plasma cleared of drug per unit

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 RENAL EXCRETION/CLEARANCE
- Determinants of extent of
renal drug excretion
o Glomerular filtration
o Tubular reabsorption
(passive
o and active)
o Tubular secretion


GLOMERULAR CAPILLARIES
- Allow passage of molecules with MW < 20,000 à glomerular
filtrate contains most of the substances RENAL EXCRETION/CLEARANCE
- Corpuscular membrane: - if there is no active secretion or reabsorption, renal clearance
o negatively charged à repels negatively charged is equal to glomerular filtration rate
molecules, including plasma proteins à drugs bound - if drug is protein bound, renal clearance = GFR x free fraction
to plasma proteins will not be filtered of drug
- renal disease affects excretion of certain drugs
PERITUBULAR CAPILLARIES o 24-hr creatinine clearance – measures extent of renal
- Most of the drug in the blood does not pass into the excretion
glomerular filtrate (because of protein binding) but passes o Cockcroft-Gault Formula – estimation of creatinine
into the peritubular capillaries in the proximal tubule clearance; overestimate of GFR
- Drug may be transported into the lumen by either of 2 § Prediction based on age, sex, creatinine, lean
mechanisms body weight
o Tubular secretion
o Tubular reabsorption CrCl (ml/min) = [(140 – age) x Lean Body Weight (kg)] /
[Serum Creatinine (mg/dL) x 72] x f
TUBULAR SECRETION f = 1 if male; f = 0.85 if female
- responsible for most renal excretion; allows clearance of
drugs bound to plasma proteins
- separate systems for weak organic acids and bases (organic COCKROFT-GAULT EQUATION*
anionic and cationic transporters)
o Competition between drugs that share the same
transport mechanism à reduced excretion
o Ex. Probenecid competes with penicillin for excretion
àpenicillin duration of action is increased
MDRD (MODIFICATION OF DIET IN RENAL DISEASE) EQUATION*












TUBULAR REABSORPTION
- depends on the fraction of molecules in the ionized state à
depends on urine pH and pKa of drug (recall the Henderson-
Hasselbalch equation) GASTROINTESTINAL EXCRETION
- ex. Aspirin overdose (note: weak acid, pKa = 3.5) - Enterohepatic circulation”
o bicarbonate à urine alkalinization à ionizes aspirin à o drug conjugate excretion into
less prone to reabsorption the bile à release into the
intestines à hydrolyzed back
into parent compound à
reabsorbed
o Prolongs the effect of the drug

VISION: 20|20 10

 SOME APPLICATIONS – METABOLISM AND EXCRETION Benzodiazepine Classification (based on half-life)
Short-acting (< 12 hr) Intermediate- Long-acting ( > 24 hrs)
acting (12-24 hrs)
Triazolam (Halcion) – 1.5 Lorazepam Nitrazepam – 16 to 38
to 5.5 hrs Midazolam – (Ativan) – 12hrs hrs Clonazepam
1.8 to 6.4 hrs Brotizolam – mean (r=9 to 16 (Klonopin) – 18 to 50
4.4 hrs hrs, n= unknown) hrs Quazepam (Doral)
Oxazepam – 4 to 14 hrs Tmax = 2hrs – 39 hrs
Loprazolam Temazepam – 8 to Diazepam (Valium) –
(Triazulenone) – 6 to 12 20 hrs 20 to 100 hrs
hrs Estazolam – 10 to Phenazepam – 60 hrs
Lormetazepam – 10 to 12 24 hrs Medazepam
hrs Alprazolam (Xanax) – Bromazepam – 12 (Nobrium) – 36 to 150
11.2 hrs (r=6.3 to 15.8) to 20 hrs hrs Prazepam – 36 to
Chlordiazepoxide 200 hrs
Ultrashort – less than 6 (Librium) – 5 to 30 Flurazepam – 40 to
hours – midazolam, hrs 250 hrs
triazolam Clobazam – 18 hrs Clorazepate –48 hrs
Nimetazepam Nordazepam
(Erimin) – 20 hrs (Nordiazepam,
Flunitrazepam Desmethyldiazepam) –
(Rohypnol) – 18 to 50 to 120 hrs
26 hrs

MATHEMATICAL ASPECTS OF PHARMACOKINETICS
KINETIC ORDER
- Related to plasma concentration of a drug; describes the rate
at which a drug leaves the body
- 2 types:
o Zero-order kinetics
o First-order kinetics
PHARMACOKINETICS OF BENZODIAZEPINES
- Liver metabolized to active compounds EXCEPT oxazepam, ZERO-ORDER KINETICS
temazepam, lorazepam (immediately conjugated) - Decrease in drug levels in the body is independent of the
- Variable half lives and durations of action plasma concentration
o Midazolam < oxazepam < temazepam < alprazolam < - Rate of elimination is held constant (fixed amount) by a
lorazepam < diazepam limiting factor (e.g., availability of an enzyme cofactor)
- Plot of plasma concentration against time – straight line
CATEGORIES OF DRUGS ACTIVE AT THE BENZODIAZEPINE - Only 3 clinically important drugs: ethanol, high dose
RECEPTOR phenytoin, high dose aspirin
- based on elimination half-lives:
o ultra-short-acting benzodiazepines: few minutes
o short-acting agents
o < 6 hours
o Triazolam, midazolam
o nonbenzodiazepine zolpidem (half-life approximately 2
hours)
o zopiclone (half-life 5 to 6 hours)
- intermediate-acting agents
o 6 to 24 hours
o estazolam and temazepam
- long-acting agents
o > 24 hours Plasma concentration vs. time plot for a drug displaying zero-order
o flurazepam, diazepam, and quazepam kinetics

FIRST ORDER KINETICS
- Majority of drugs
- Decrease in drug levels in the body is dependent on the
plasma concentration (i.e., rate of elimination is
proportionate [fixed fraction/percentage] to plasma
concentration), since the concentration of the substrate
(drug) is the rate-limiting factor

VISION: 20|20 11

 - Plot of plasma concentration against time – exponential t½ = 0.693 x (Vd / Cl) or t½ = (0.693 x Vd)/ Cl
t½ = 0.693 / Kel

- related to Vd, but does not determine the ability of the body
to remove the drug from the
- circulation, since both Vd and half-life change in the same
direction
- can also be derived from graphs of plasma concentration
versus time (see discussion of half- life in the section in the
two-compartment model)




Plasma concentration vs. Time plot for a drug displaying first-
order kinetics





Log plasma concertation vs. Time plot compatible with one-
compartment open pharmacokinetic model for drag disposition
after a parenteral dose, assuming first-order kinetics (Kel =
elimination rate constant, C0 = initial drug concentration, t1/2 = half
life)

HALF-LIFE






ONE-COMPARTMENT MODEL
- Clearance – the body’s ability to remove a drug from the
First order vs. Zero-order elimination blood; constant for individual drugs
o Volume of blood cleared of the drug per unit time
COMPARTMENT MODELS
ONE-COMPARTMENT MODEL
Clp = Vd x Kel
- Widely used to determine the dose of the drug to be
Where Kel is the elimination constant
administered
Cl = rate of elimination of drug /plasma drug
- Considers the body as a single compartment à drug is
absorbed, immediately distributed, and subsequently concentration
Total Body Cl = Cl + Cl + Cl + Cl
eliminated by metabolism and excretion hepatic renal pulmonary other
- If the volume of the compartment is Vd and the dose
administered is D, then the initial drug concentration will be: CLEARANCE


C0 = D/Vd



- Half-life – time taken for the plasma concentration to fall to

half (applicable only to drugs undergoing first-order

elimination) after complete absorption and distribution
If the drug is not administered parenterally, plotting the log plasma
- Decline in concentration may be exponential, but expressed
drug concentration against time will require the consideration of
graphically as a straight line when the log plasma
both absorption and elimination from the compartment
concentration is plotted against the time after an
intravenous dose
- Half-life
o related to the elimination rate constant (Kel) by the
following equation:

t½ x Kel = natural log 2 (ln2)

VISION: 20|20 12

 MODEL-INDEPENDENT APPROACH
- Css = plasma concentration of the drug at steady state (for
drugs displaying first-order kinetics) à the level of the drug
in the body increases until it is equal to the level excreted
- Rate of drug influx into the body = rate of drug elimination out
of the body




Log plasma drug concentration vs. plot of a drug compatible with
the one-compartment pharmacokinetic model for drug disposition
after an oral dose (Kel = elimination rate constant, C0 = initial drug
concentration, t1/2 = half life)

TWO-COMPARTMENT MODEL
- Drug distribution between the peripheral compartment
(tissues) and the central compartment (plasma) occurs at Log plasma concentration vs. time plot for a drug administered by
varying rates (rapid à insignificant) mouth every 6 hours when terminal disposition half-life is 6 hours
- Curvilninear relationship between the log of plasma
concentration and time (2 phases) - During constant infusion, half- life = % of
o α-phase – early, rapid; represents the redistribution of steady state
the drug to the peripheral compartment and a modest o • 1 – 50
component of elimination o • 2 – 75
o β-phase – later, slower; combination of elimination and o • 3 – 87.5
return of the drug from the peripheral compartment o • 4 – 94
to the central compartment, in which the drug - amount of drug in the body at steady-state will depend on the
distributes rapidly frequency of drug administration
o greater frequency à greater amount of drug à less
variation between peak and trough plasma
concentration
o accumulation of the drug will occur if the frequency of
administration is greater than the half-life
o if infusion rate/dosing interval is doubled, steady state
concentration is also doubled because dose and
concentration are directly proportional (linear
kinetics); Css x
- Loading dose – can be calculated according to the desired
plasma concentration at steady-state (Css) and the volume of
Log plasma concentration vs. time plot that requires a two- distribution (Vd) of the drug
compartment open model to account for its disposition after a
parenteral dose. (Kel = elimination rate constant) Loading dose (mg/kg) = Vd (L/kg) x Css (mg/L)
Therefore, Vd = Loading dose / steady-state plasma
Half-life may also be derived from this model using graphs of plasma concentration
concentration versus time (see Figure 9) by measuring the time for a
50% decrease in the elimination phase PHARMACOKINETIC INTERACTIONS
- absorption, distribution, metabolism, and excretion all affect
pharmacokinetic properties of drugs; any drug that interferes
with these processes will be altering the effect of other drugs

Dosage Regimens
- Calculations require target therapeutic plasma concentration
and PK parameters of the drug
- Loading dose - fill the volume of distribution to achieve target
plasma concentration;
o Stays the same despite impaired renal and hepatic
function
Loading dose = (Vd x Cp [target])/F
Typical drug plasma concentration vs. time curve after intravenous F = 1 if 100% oral bioavailability
injection (note: concentration axis is logarithmic)

VISION: 20|20 13

 LOADING DOSE significant
- if partly cleared partly by the kidney and partly by other
routes, equation should be applied to the part of the dose that
is eliminated by the kidney
o ex. Drug is 50% cleared by kidneys, 50% by the liver;
normal dosage: 200 mg/d; therefore, hepatic and
renal elimination rates are each 100 mg/d.
Dosage Regimens o if the patient’s creatinine clearance of 20 mL/min:
- Maintenance dose (rate; mg/hr)- replace the drug that is
being eliminated by the body over time to maintain a steady Dosage = 100 mg/d (liver) + [100 mg/d x (20 ml/min / 100
target plasma concentration (involves clearance) ml/min)](kidney)
o decreases with impaired renal or hepatic function
Dosage = 100 mg/d + 20 mg/d = 120 mg/d
Maintenance dose = (Cl x Cp [target])/F
For IV infusion: CORRECTED DOSAGE
infusion rate (k0) =rate of elimination (at steady state)
k0 = Cl x Css

For oral administration:
Maintenance dose = (Cl x Css x τ)/F
where τ (tao) = dosing interval (hours)
- Further Drug Classification 

MAINTENANCE DOSAGE - Pregnancy Category
o A, B, C, D, X 

- Controlled drugs

o Closely monitored by the Dangerous Drugs Board of

the DOH

o Need S-2 license

Dosage Regimens o Prescription in triplicate 

- Dosing interval for maintenance dosing is based on t½such that
peak and trough concentrations do not vary excessively form FDA Pregnancy Categories
target Cp - A- Adequate studies in pregnant, no risk 

- Most oral drugs are given one or more times a day but rarely - B- Animal studies show no fetal risk, but human studies
more than 4 times a day 
are not adequate OR Animal toxicity but human studies
- Drugs with short t½ may have to be given by a different route 
show no risk 

(IV) orin the form of slow- or extended-release oral - C- Animal studies show toxicity, human studies inadequate
formulations

but benefit of use may exceed risk 


- D- Evidence of human risk, but benefits outweigh risks 

Correction for Dosage Regimens
- X- Fetal abnormalities in humans, risk greater than benefit
- May be necessary to account for variations in PK

- Clearance may be significantly affected by disease (renal or

hepatic failure)

- Volume of distribution is rarely changed significantly by

disease



ADJUSTMENT OF DOSAGE WHEN ELIMINATION IS ALTERED BY

DISEASE

- Renal disease or reduced cardiac output à reduces the

clearance of drugs that depend on renal function

- Less common - alteration of clearance by liver disease

o occurs (for high extraction drugs) in the following states:

§ reduced liver blood flow (i.e., heart failure)

§ severe cirrhosis and other forms of liver failure



CORRECTION OF DOSAGE IN A PATIENT WITH RENAL IMPAIRMENT

- average dosage for a normal person multiplied by the ratio of

the patient’s altered creatinine clearance (CLcr) to normal

creatinine clearance (approximately 100 mL/min, or 6 L/h)



Corrected dosage =Average dosage x (Patient’s

ClCr)/(100 ml/min) Notes from Lecture PPT, and Manual ONLY
- limitation: ignores non-renal routes of clearance that may be

VISION: 20|20 14