Equations and physiological values

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UNIVERSITY OF SOUTH AUSTRALIA
SCHOOL OF PHARMACY AND MEDICAL SCIENCES
PHARMACOKINETICS AND BIOPHARMACEUTICS 201
TIME: 2 HOURS
General Instructions to Candidates Name _____________________
Student Number _____________
Answer all questions in the spaces provided.
Calculators may be used
Graph paper is provided. Please write your name on the graph paper.
A list of symbols and equations is provided
The mark allocated to each question is shown in the table below.
Please ensure that your answers are in the correct units.
For examiners use only

Question	Value	Mark
1	30
2	20
3	20
4	20
5	10

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Equations and physiological values
Glomerular filtration rate = 120 mL/min
Hepatic blood flow = 1.5 L/min
Renal blood flow = 1.2 L/min
Cardiac output = 5 L/min
Haematocrit = 0.5
Plasma concentrations after an intravenous bolus
– monoexponential C = C(0).exp-k.t
– biexponential C = A.exp-.t + B.exp-.t
Plasma concentrations during an intravenous infusion (monoexponential only)
C = (Ro/CL).(1-exp(-k.t))
where Ro is the zero-order infusion rate
Plasma concentrations after an extravascular dose
Half-life
Physiological determinants of clearance and volume of distribution
Hepatic clearance
Renal clearance
Volume of distribution
Pharmacodynamic response
Accumulation Index
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1. Pumperol, is being developed for use in the treatment of peripheral vascular
disease. In a Phase 1 study, the drug was administered as a single intravenous bolus
(100mg) and a single oral dose (200mg) to male volunteers. The oral dose consisted
of a dry powder pl inside a gelatin capsule. The following plasma concentrationtime data were obtained.

Plasma Conc (mg/L)
Hours	IV (100mg)	Oral (200mg)
0.5	1.51	0.21
1	1.36	0.33
1.5	1.23	0.39
2	1.12	0.42
3	0.91	0.41
4	0.75	0.36
6	0.50	0.26
8	0.34	0.18
10	0.23	0.12
12	0.15	0.08

Urine was collected for 24 hours after intravenous dosing and was found to contain
0.3 mg of unchanged drug. The fraction unbound in plasma was 0.15 and this was
independent of concentration (0.1 to 10mg/L). The blood-to-plasma concentration
ratio was 0.65.
(a) Plot the data, and
(b) Calculate the following pharmacokinetic parameters
(i) Elimination half-life
(ii) Volume of distribution
(iii) Clearance
(iv) Renal Clearance after the intravenous dose
hours
L
L/h
mL/min
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Question 1 (continued)
(c) Determine the equation that describes the plasma concentration versus time profile
of the drug after oral administration.
(d) Calculate the absolute bioavailability of the drug after administration of the oral
capsule
(e) Based upon your previous answers, what can you conclude about the extent of
absorption of the drug from the gastrointestinal tract and the factors that are most
likely to be affecting the extent of absorption?
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2. Lignocaine is an antiarrhythmic agent with the following pharmacokinetic
properties (taken from APF, 18th Edition)
Half-life = 2 hours
Clearance = 10 mL/min/kg
The APF also tells us that lignocaine is a drug with a ‘low therapeutic index’ and as
such should be monitored. The optimal plasma concentration range for lignocaine is
1.5 to 5.0 mg/L.
As a pharmacist working on a cardiac ward, you have been asked to check the
following prescription which was ordered for a 50kg patient experiencing a cardiac
rhythm problem.

Rx	Lignocaine to be given as a single intravenous bolus of 600mg followed by a continuous intravenous infusion of 5 mg per min.

(a) Calculate the plasma concentration you would expect in this patient (show your
calculations below)
(i) just after the initial bolus dose
(ii) at steady state
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2 (b) based on your answers to part (a), what is your judgement regarding the safety
of the prescribed dosage regimen for lignocaine in this patient. If you think the dose
should be changed (and this does not imply that a change is necessary), then you
should make an appropriate recommendation.
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3. (a). Provided below is information on the physicochemical and biopharmaceutical
properties of erythromycin and griseofulvin. Using this information, briefly discuss
how the administration of these drugs with a high fat meal would influence the rate
and the extent of their oral absorption. In your answer, discuss the effects of a high fat
meal on gastric emptying and discuss the clinical implications of this.

Erythromycin	Griseofulvin
Indication	Antibiotic	Antifungal
Stability in gastric acid	Acid labile	Stable
Solubility	Poorly water soluble (very lipophilic)	Poorly water soluble (very lipophilic)
Oral bioavailability of an oral solution	Low (about 0.4)	Low (<0.5 without food)

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3. (b). Briefly describe the principle of a transdermal delivery system. Discuss the
important factors that need to be considered for a drug to be administered as a
transdermal patch. Throughout your answer, provide examples where relevant.
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4.

Atenolol	Diltiazem	Methotrexate
Acid/Base category	Weak base	Weak base	Weak acid
pKa	9.6	7.7	3.5
Octanol to water partition coefficient	0.1	1000	0.1
Oral Bioavailability	0.5	0.25	0.8
Clearance (mL/min)	150	600	200
Renal clearance (mL/min)	75	3	150
Is renal clearance reduced by probenecid?	No	No	Yes
Fraction unbound in plasma	0.95	0.05	0.3

Notes: –
The octanol-to-water partition coefficient is a measure of lipophilicity
Probenecid is an organic anion and a known inhibitor of renal tubular secretion.
All clearance measurements are with respect to plasma
For all drugs the blood to plasma partition coefficient is about 0.5
For each of the three drugs, comment on
(a) renal clearance mechanism and factors that are likely to alter renal clearance

Atenolol

Diltiazem

Methotrexate

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(b) in what way (if any) a reduction in the plasma levels of the major drug binding
proteins (including albumin and glycoproteins) would alter the pharmacokinetics.

Atenolol

Diltiazem

Methotrexate

(c) how the pKa and lipophilicity of each drug may be affecting its specific
pharmacokinetic properties

Atenolol

Diltiazem

Methotrexate

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5. Nonlinear pharmacokinetics can occur during the absorption, distribution,
metabolism and excretion (ADME) of drugs. For each stage of ADME provide:
– one example of a drug that exhibits nonlinear pharmacokinetics,
– an explanation of why your chosen drug displays nonlinear pharmacokinetics,
– a discussion of the clinical implications of your example.

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