A pharmaceutical company is developing a new drug ‘FCP-17′ and has just determined the following pharmacokinetic parameters from a Phase I human study:
Fraction unbound (fu): 0.5
Clearance by active secretion (CLsec): 2L/hr
Fraction reabsorbed (FR): 0.25
Hepatic Extraction Ratio (EH): 0.25

Question:
Showing all working out, and stating all assumptions, Calculate the total SYSTEMIC CLEARANCE for ‘FCP-17’.

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Inter-Individual Variability
A pharmaceutical company has convinced your paramedic service to add their new orally administered opioid analgesic ‘fucpoaphine’ to their formulary. Fucpoaphine requires hepatic activation in order to elicit an analgesic effect. Studies in healthy volunteers have demonstrated that fucpoaphine is rapidly activated (within 2minutes) following oral administration and that the sole enzyme involved in the activation of fucpoaphine is CYP2C19.

Questions:
a) Select ONE specific factor (environmental, genetic or physiological) that may contribute to inter-individual variability in the activation of fucpoaphine, and explain the potential consequences of this variability in terms of treatment response and tolerability. (200 words)

b) Identify a strategy to account for variability in fucpoaphine activation that can be used in a pre-hospital situation and briefly explain how this strategy could be used to optimise treatment response and tolerability. (100 words)