2.4 Liver metabolism
The clearance of the drug by the liver was calculated from the intrinsic
clearance of the drug by CYP3A4 enzyme for RPV and by UGT1A1 and UGT1A9
enzymes for cabotegravir [40]. The intrinsic clearance of the drug
by each enzyme were scaled to the whole of liver using the microsomal
protein content per gram of liver (MPPGL) and the weight of the liver.
The intrinsic clearance for RPV and CAB were calculated using equations
3 and 4 respectively: z
\(\text{Cl}_{\text{CYP}3A4,\text{liver}}\ =\ \text{Cl}_{\text{int},\text{CYP}3A4,\text{liver}}\ \times\text{Abundance}\ \times\text{MPPGL}\ \times\ {\text{Weig}ht}_{\text{liver}}\)(3)
\(\text{Cl}_{\text{UGT},\text{liver}}\ =\ \text{Cl}_{\text{int},\text{UGT},\text{liver}}\ \times\text{MPPGL}\ \times\ {\text{Weig}ht}_{\text{liver}}\)(4)
where ClCYP3A4,liver is the hepatic clearance by CYP3A4
enzyme in L/hr; Clint,CYP3A4,liver in µL/min/pmol, is
the intrinsic clearance by a CYP enzyme; ClUGT,liver is
the hepatic clearance by a UGT enzyme in L/hr;
Clint,UGT,liver in µL/min/mg, is the intrinsic clearance
per milligram of microsomal protein; Abundance is the enzyme abundance
of CYP3A4 per milligram of microsomal protein (pmol/mg); MPPGL is the
milligram of microsomal protein per gram of liver (mg/g) and
Weightliver is the weight of the liver [32].
The total hepatic clearance of the drug in the liver
(Clh) was used to calculate the fraction of the drug
reaching the systemic circulation from the liver as described in
equation 5:
\(F_{h}\ =\ \frac{Q_{h}}{Q_{h}\ +(\text{Cl}_{h}\times\ \frac{\text{fup}}{R})}\)(5)
where Fh is the fraction of the drug escaping hepatic
metabolism and entering the systemic circulation from the liver,
Qh is the rate of blood flow to the liver,
Clh is the total hepatic clearance of the drug in the
liver, fup is the fraction of the unbound drug in plasma
and R is the tissue-to-plasma partition of the drug in the liver.