COLLEGE OF PHARMACY 3/F St. Therese Bldg. 900 San Marcelino St. 1000 Ermita, Manila Tel. No.: (02) 521-2621 (02) 524-2011 local 390
Biopharmaceutics and Pharmacokinetics MIDTERM EXAMINATION
General Instructions: Use blue or black ink only. STRICTLY NO ERASURES of any sort. You may use you test questionnaire as your scratch. CHEATING OF ANY FORMS is strictly PROHIBITED. If you have conc erns, do not talk to your classmates. Ask the instructor/proctor. Anyone caught cheating will automatically get a score of zero (0) in the exam. 1. The rate of drug transport across a cell membrane by lipid diffusion depends on all of the following EXCEPT: a. Drug size (diffusion constant) b. Surface area of absorption c. Density of transporters d. Concentration gradient 2. A characteristic of absorption by lipid diffusion is its saturability at high drug concentrations. a. True b. False 3. Drugs with low oil: water partition coefficients undergo lipid diffusion more rapidly than drugs with high oil:water partition coefficients. a. True b. False 4. The following IV administration, drugs are distributed fastest to: a. The skin, kidney, and brain b. The liver, kidney, and brain c. The liver, adipose, and brain d. The liver, kidney, and adipose e. The adipose, skin, and brain 5. A fundamental characteristic of all first order pharmacokinetic process is that the rate of the process is proportional to drug concentration: a. True b. False 6. Competition between two drugs for binding to plasma protein(s) can result in the change in the concentration of free drug and potential drug toxicity. a. True b. False 7. At pH 9.0, morphine (a weak base containing an ionizable amine group, pKa of 7.0) would exist predominantly in the charged form. a. True b. False 8. At pH 5.0, the ratio of the protonated to unprotonated forms of morphine (a weak base containing an ionizable amine group, pKa=7.0) would be: a. 1:100
9.
10.
11.
12.
13.
14.
15.
b. 1:10 c. 10:1 d. 100:1 A characteristic of drugs eliminated by zero order kinetics processes is that halflife is not constant. a. True b. False The plasma drug concentration versus time curve for a drug eliminated by zero order kinetics is linear. a. True b. False Drug metabolism is the process that converts chemicals into less polar metabolites so that they are more difficult to excrete. a. True b. False All of the following are examples of Phase I drug metabolizing reactions EXCEPT: a. N-dealkylation of theophylline b. Aliphatic oxidation of pentobarbital c. Hydrolysis of succinylcholine d. Glucuronidation of acetaminophen e. Reductive dehalogenation of halothane The termination of action of the preanesthetic muscle relaxant, succinylcholine is markedly affected by: a. Redistribution from the brain to the adipose tissue b. Enzyme induction c. Enzyme inhibition d. Pharmacogenetic factors For a drug that is eliminated primarily by renal glomerular filtration, the theoretical maximum clearance is approximately: a. 1-2 mL/min b. 12 mL/min c. 120 mL/min d. 1250 mL/min’ The volume of distribution of gentamicin, a highly polar water-soluble Page 1 of 5
COLLEGE OF PHARMACY 3/F St. Therese Bldg. 900 San Marcelino St. 1000 Ermita, Manila Tel. No.: (02) 521-2621 (02) 524-2011 local 390
16.
17.
18.
19.
20.
21.
drug, is 14L per 70 kg. This reflects the distribution of gentamicin into: a. Plasma b. Plasma and blood c. Plasma, blood, and interstitial fluid (extracellular water) d. Total body water First order kinetics, EXCEPT a. Means rate of reaction is proportional to concentration b. Are more common than zero order kinetics c. Apply to exponential processes d. Generally apply to high plasma concentrations (>20mg/100ml) of ethanol e. Result in steady state concentrations after multiple dosing . Pharmacokinetics is: a. The study of biological and therapeutic effects of drugs b. The study of absorption, distribution, metabolism and excretion of drugs c. The study of mechanisms of drug action d. The study of methods of new drug development What kind of substances can’t permeate membranes by passive diffusion? a. Lipid-soluble b. Non-ionized substances c. Hydrophobic substances d. Hydrophilic substances What does the term “bioavailability” mean? a. Plasma protein binding degree of substance b. Permeability through the brainblood barrier c. Fraction of an uncharged drug reaching the systemic circulation following any route administration d. Amount of a substance in urine relative to the initial doze Which route of drug administration is most likely to lead to the first-pass effect? a. Sublingual b. Oral c. Intravenous d. Intramuscular Parenteral administration:
22.
23.
24.
25.
26.
27.
a. Cannot be used with unconsciousness patients b. Generally results in a less accurate dosage than oral administration c. Usually produces a more rapid response than oral administration d. Is too slow for emergency use The volume of distribution (Vd) relates: a. Single to a daily dose of an administrated drug b. An administrated dose to a body weight c. An uncharged drug reaching the systemic circulation d. The amount of a drug in the body to the concentration of a drug in plasma Biotransformation of the drugs is to render them: a. Less ionized b. More pharmacologically active c. More lipid soluble d. Less lipid soluble Metabolic transformation (phase 1) is: a. Acetylation and methylation of substances b. Transformation of substances due to oxidation, reduction or hydrolysis c. Glucuronide formation d. Binding to plasma proteins Biotransformation of a medicinal substance results in: a. Faster urinary excretion b. Slower urinary excretion c. Easier distribution in organism d. Higher binding to membranes An example of a situation that would not support therapeutic drug monitoring with plasma drug concentration would be one in which: a. A wide variation in plasma drug concentration is achieved in different patients given a standard drug dose b. The toxic plasma concentration is many times the therapeutic concentration range c. Correlation between a drug’s plasma concentration and therapeutic response is positive. For a drug with a narrow therapeutic index the plasma concentration required for their therapeutic effects is near the Page 2 of 5
COLLEGE OF PHARMACY 3/F St. Therese Bldg. 900 San Marcelino St. 1000 Ermita, Manila Tel. No.: (02) 521-2621 (02) 524-2011 local 390
concentration that produces toxic effects. a. True b. False 28. Highly perfused organs and blood comprise what is usually known as peripheral compartment. a. True
b. False 29. The volume of distribution equals ______ divided by the initial drug concentration. a. Clearance b. Initial drug concentration c. Half-life d. Dose
Match the drugs with their corresponding indications 30. Chloramphenicol A. Anticoagulant 31. Colchicine B. bronchial asthma 32. Digoxin C. HIV infection 33. Zidovudine D. CHF with atrial fibrillation 34. Minoxidil E. Non-Hodgkin’s lymphoma 35. Methotrexate AB. Typhoid infection 36. Theophylline AC. Multiple sclerosis 37. Phenytoin AD. Acute gout 38. Corticosteroid AE. Status epilepticus 39. Vancomycin BC. Baldness 40. Warfarin BD. MRSA infection Match the drug with their corresponding adverse effects. 41. Chloramphenicol A. fetal hydantoin syndrome 42. Phenytoin B. Oral thrush 43. Corticosteroids C. hirsutism 44. Minoxidil D. Gray Baby syndrome 45. Warfarin E. Purple toe syndrome Match the pharmacokinetic studies undertaken with each stage of pharmaceutical product development. 46. Preclinical studies A. Biochemical studies 47. Phase I Clinical studies B. Fundamental pharmacokinetics 48. Phase II Clinical studies C. Pharmacokinetic parameters in patients 49. Phase III Clinical Studies D. Population pharmacokinetics 50. Phase IV Clinical studies E. Post-marketing surveillance
Part II. Problem Solving. Write all the necessary computations. Round-off your answers to 4 decimal places. BOX YOUR FINAL ANSWER. (5 points each) 1. Drug Y is given by an intravenous injection and plasma concentration are then determined as follows: Time after injection Concentration (hours) (mg/L) 0 12 1 9.8 2 7.9 3 6.4 4 5.2 5 4.2 6 3.4 7 2.8 8 2.2 Compute for the following: a. Does the decrease in the amount of drug A appear to be a zero-order or first-order reaction? Provide evidence for your answer.
Page 3 of 5
COLLEGE OF PHARMACY 3/F St. Therese Bldg. 900 San Marcelino St. 1000 Ermita, Manila Tel. No.: (02) 521-2621 (02) 524-2011 local 390
b. What is the rate constant k? c. What is the half-life t1/2? 2. Theophylline is effective in the treatment of bronchitis at a blood level of 10-20mcg/ml. at therapeutic range, theophylline follows first-order kinetics. The average t 1/2 is 3.4 hours, and the range is 1.8 to 6.8 hours. The average volume of distribution is 30 L. a. The renal clearance of theophylline is 0.36 L/hr. what are the km and k e assuming all nonrenal clearance is due to metabolism? 3. The initial plasma concentration of a drug given IV at 9:00am is 250 mg/ml. If the half-life of the drug is 6 hours, perform a calculation to predict the plasma concentration will be at 9:00pm s ame day. 4. The data in represent the average findings in antibiotic plasma samples taken from 10 humans (average weight 70 kg), tabulated in a four -way crossover design.
Time after Dose (hr) 0.5 1.0 1.5 2.0 3.0 4.0 6.0 8.0 10.0 12.0
( × ℎ)
IV Solution (2 mg/kg) 5.94 5.30 4.72 4.21 3.34 2.66 1.68 1.06 0.67 0.42 29.0
Plasma Concentration ( μg/ml) Oral Solution Oral Tablet Oral Capsule (10 mg/kg) (10 mg/kg) (10 mg/kg) 23.4 13.2 18.7 26.6 18.0 21.3 25.2 19.0 20.1 22.8 18.3 18.2 18.2 15.4 14.6 14.5 12.5 11.6 9.14 7.92 7.31 5.77 5.00 4.61 3.64 3.16 2.91 2.30 1.99 1.83 145.0
116.0
116.0
a. From which oral drug product is the drug absorbed more rapidly? b. What is the absolute bioavailability of the drug from the oral solution? c. What is the relative bioavailability of the drug from the oral tablet compared to the reference standard? d. What is the total body clearance?
Formula:
= −0 + 0 ln = − + 0 = × =
Page 4 of 5
COLLEGE OF PHARMACY 3/F St. Therese Bldg. 900 San Marcelino St. 1000 Ermita, Manila Tel. No.: (02) 521-2621 (02) 524-2011 local 390
EXAMINATION ANSWER SHEET
Part II. Problem Solving.
Page 5 of 5
