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.