Question 1 (25 points)
The pharmacokinetics, metabolism, and excretion of Compound A, a MEK inhibitor, were characterized in healthy male
subjects (n = 6) following a single 20 mg (200 PCi) oral dose. Unchanged Compound A and metabolites were identified by
LC-MS. Compound A accounted for 21% of the drug-related material in plasma up to 48 hours postdose; it had a
terminal plasma half-life of 75.5 h. Multiple hydroxylated and glucuronidated metabolites were identified in plasma,
urine and feces, with only 2% and 6% unchanged Compound A in urine and feces, respectively (Fig 1).
Fig 1: Structures of Compound A and its metabolites
Fig 2A shows the concentration-time profiles of total radioactivity (solid squares) and Compound A (open diamonds) in
plasma following a single oral dose of [14C]Compound A (20 mg, 200 PCi). Fig 2B shows the recoveries of radioactivity in
urine (open diamonds), feces (open squares) and total recovery (black squares).
The fraction of administrated 14C absorbed was 88%, while the absolute bioavailability of Compound A was determined
to be 28%. Notably, a PK modeling program gave a good fit for the plasma concentrations of Compound A after IV
administration but did not adequately model the oral data (Fig 3).
Fig 3: Panel A illustrates the observed PK profile of Compound A in plasma (data points) after IV administration of 2 mg
and the computed fit (red line). Panel B shows the plasma concentrations after 20 mg oral dose (data points) and the
computed fit (black line).
A. How would you account for the effective absorbance of radioactivity in this oral administration study, compared
with the relatively low bioavailability (28%) of Compound A. Specify what may be happening and what may be
causing it (8 points)
B. How would you account for the extensive metabolism of Compound A in comparison to its long plasma half-life?
Based on the data provided, provide a quantitative estimate of the clearance from plasma. (8 points)
C. Design in vitro experiments to further the understanding (mechanistic basis) of Compound A pharmacokinetics in
vivo. (9 points)

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