Updated: 5/27/2021

Pharmacokinetics

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Volume of Distribution (Vd)
  • Volume of distribution (Vd) relates amount of drug in body to plasma concentration
  • Vd = (amount of drug in the body) / (plasma drug concentration)
  • Vd is changed in disease states that decrease plasma proteins
    • a decrease in plasma proteins decreases binding of drug to plasma proteins
      • Vd of drugs
    • e.g., liver disease
      • via ↓ protein synthesis
    • e.g., kidney disease
      • via urinary protein loss
  • Vd increased in disease states that increase total body water
    • ascites, pulmonary edema, heart failure
    • can lower plasma concentration of water soluble drugs 
  • Vd predicts drug distribution in body
    • low Vd drugs
      • 4-8 L
      • drugs distribute in vascular compartment (blood) and bind plasma proteins
      • drugs are large and/or charged molecules
    • medium Vd drugs
      • drugs distribute in extracellular compartment and/or total body water
      • drugs are small, hydrophilic molecules that do not bind plasma proteins 
    • high Vd drugs
      • > body weight
      • drugs distribute in all tissues
      • drugs are small, lipophilic molecules that bind strongly to extravascular proteins
Clearance (CL)
  • CL = (rate of elimination of drug) / (plasma drug concentration) = Vd * Ke
    • Ke = elimination constant
  • CL relates the rate of elimination to the plasma concentration
Half-Life (t1/2)
  • t1/2 = (0.7 * Vd)/CL
  • half-life is time required for amount of drug to fall to 50% of an earlier measurement during elimination or during constant infusion
    • a drug infused at a constant rate reaches about 94% of steady state after 4 half lives  
  • for drugs eliminated by first-order kinetics, half-life is constant regardless of concentration
# of half lives 1 2 3 4
Concentration 50% 75% 87.5% 93.75% 
Bioavailability (F)
  • bioavailability is the fraction of administered dose that reaches systemic circulation
  • bioavailability is defined as unity, or 100%, in case of IV administration
  • bioavailability of drug administered by other routes is generally reduced by incomplete absorption, first-pass metabolism, and any distribution into other tissues that occurs before the drug enters systemic circulation
    • e.g., orally, F = percent that is absorbed and survives first-pass metabolism in liver
  • Calculation of bioavailabillity (F) = 100% * (AUC-oral * Dose-IV) / (AUC-IV * Dose-oral), where AUC is the area under the curve of a pharmacokinetic plasma concentration versus time plot  
  • delayed release formulations will have slower rise and lower peak compared with rapid release formulations 

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Questions (5)
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(M1.PH.15.75) An experimental infusable drug, X729, is currently being studied to determine its pharmacokinetics. The drug was found to have a half life of 1.5 hours and is eliminated by first order kinetics. What is the minimum number of hours required to reach a steady state concentration of >90%?

QID: 106861
1

1.5

4%

(6/139)

2

3

10%

(14/139)

3

4.5

26%

(36/139)

4

6

54%

(75/139)

5

7.5

2%

(3/139)

M 1 D

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(M1.PH.15.75) A pharmaceutical company is attempting to determine the bioavailability of a new glucose-lowering agent, Compound X, they have developed. They have previously studied the pharmacokinetics of both IV and oral forms of this drug. The company has obtained the following information regarding the IV formulation of Compound X: Administration of 50 mg of Compound X by IV yields an area under the curve (AUC) on a plasma drug concentration versus time plot of 60 mg hr/L. Additionally, the company has also obtained the following information regarding the oral formulation of Compound X: Administration of 100 mg of Compound X by a PO route yields an AUC on a plasma drug concentration versus time plot of 80 mg hr/L. Which of the following is the absolute bioavailability of Compound X?

QID: 106854
1

58%

5%

(11/206)

2

64%

12%

(24/206)

3

67%

50%

(102/206)

4

70%

17%

(35/206)

5

74%

10%

(20/206)

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(M1.PH.13.89) A 65-year-old female patient with a past medical history of diabetes mellitus and an allergy to penicillin develops an infected abscess positive for MRSA on the third day of her hospital stay. She is started on an IV infusion of vancomycin at a dose of 1000 mg every 12 hours. Vancomycin is eliminated by first-order kinetics and has a half life of 6 hours. The volume of distribution of vancomycin is 0.5 L/kg. Assuming no loading dose is given, how long will it take for the drug to reach 94% of its plasma steady state concentration?

QID: 100605
1

6 hours

4%

(14/336)

2

12 hours

12%

(40/336)

3

18 hours

19%

(65/336)

4

24 hours

52%

(176/336)

5

30 hours

7%

(25/336)

M 1 D

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