PK

Question 1

sides of a hepatocyte

Answer 1

1) basolateral: contact with blood
2) apical: contact with sinusoids

Question 2

factors affecting drug distribution into hepatocytes

Answer 2

1) perfusion rate limited
- most drugs rapid diffusion from sinusoidal blood into hepatocytes (reach equilibrium fast)

2) permeability rate limited
- for large/polar drugs

Question 3

what does low Eh mean?

Answer 3

permeability rate limited

Question 4

what does high Eh mean?

Answer 4

perfusion rate limited

Question 5

when there is high Eh, what changes when fu changes?

Answer 5

since it is perfusion rate limited, CL and Eh minimally affected by changes in fu

Question 6

when there is low Eh, what changes when fu changes?

Answer 6

since it is permeability rate limited, CL and Eh are affected by changes in fu

Question 7

what are the assumptions for well-stirred model

Answer 7

1) once drug enters it is distributed instantaneously since liver is 1 homogenous model so no diffusion delay

Question 8

equations for CLb, h for well-stirred model

Answer 8

1) high Eh: perfusion rate limited
CLb, h = Qh

2) low Eh: capacity rate limited
CLb, h = fub x CLint

Question 9

effect of increases in fu on C and Cu for high Eh

Answer 9

C: unchanged because C includes both bound and unbound so total C increases
Cu: increases because more fu and Eh and CLb,h remains the same

Question 10

effect of increases in fu on C and Cu for low Eh

Answer 10

C: decreased cuz CLb, h and Eh increases so more is cleared

Cu: unchanged because CLb, h and Eh increases accordingly to clear the extra fu

Question 11

factors affecting renal clearance (CLr) - urine flow

Answer 11

• water extremely reabsorbed -> drug concentrate in urine -> favours reabsorption of drug cuz of concentration gradient
• faster urine flow = lesser time for reabsorption = increase CLr
• only for drugs that are mostly reabsorbed
• diuresis (for poisoning) -> input > fluid -> pass out urine -> excrete drugs

Question 12

factors affecting renal clearance (CLr) - urine pH

Answer 12

• urine pH = 6.4 (4.4 - 7.9)
• factors that affect pH: forced acidification/alklalinsation, diet, clinical state
• polar/non-polar acid/base drug excreted ionised/unionised depending on pH and pKa
• differences in degree of ionisation for polar drugs
  1) very weak acid/base: largely unionised, extensively reabsorbed, low CLr
  2) weak acid (moderate-low pKa): CLr sensitive to pH
  3) weak base (moderate-high pKa): CLr sensitive to pH, minimally/extensively reabsorbed depending on pH
• differences in degree of ionisation for nonpolar drugs
  1) not reabsorbed in unionised form so not affected by urine pH

Question 13

DDI involving metabolism - enzyme inhibition

Answer 13

• increase toxicity
• competitive vs non-competitive inhibition
• reversible (remove perpetuator drug) vs irreversible (need time for body to remove drug) inhibition
• mechanism based/irreversible inactivation: metabolism produce reactive intermediate that irreversibly inactivate enzyme, body need time to produce more enzyme

Question 13

DDI involving metabolism - enzyme induction

Answer 13

. inducer (perpetuator drug) increases de novo RNA & protein synthesis to generate more CYP
- e.g. enter hepatocyte to bind to/activate nuclear receptors

. inducer stabilise translation/inhibition of protein degradation pathway (2E1)

Question 14

DDI involving excretion

Answer 14

. glomerular filtration: molecular filtration: competition for protein binding, alterations to renal blood flow
. tubular secretion: active process: compete for active transport
. tubular reabsorption: passive process: alteration in urine pH affect ionisation of drug

Question 15

why is IV good?

Answer 15

1) direct into systemic circulation, faster
2) maintain constant plasma drug concentration, prevent fluctuations, good for drugs with narrow TI

Question 16

assumptions for constant rate IV infusion

Answer 16

1) 1st order
2) 1 compartment
3) rate of change of drug = constant infusion rate - rate of elimination

Question 17

how does amount of drug in body, elimination rate and rate of change of drug in body change over time for IV bolus

Answer 17

I: when IV just start
- amount of drug in body = 0
- elimination rate = 0 (since no drug)
- rate of change of drug is at the max

II: in the middle before steady state
- amount of drug in body increasing
- elimination rate increases
- slower rate of change in drug in body since infusion constant but elimination decreases

III: steady state
- amount of drug in body constant (Ass)
- elimination rate = infusion rate
- rate of change of drug in body = 0