TABLE 2.

Mechanisms Behind Altered PKs in Patients With Cirrhosis and PH

	Mechanism	Comments
1	Reduced intrinsic capacity  - Decreased enzyme levels  - Decreased activity	Liver disease etiology–specific variability in different CYPs may exist—for example, alcohol and infection can affect some CYPs selectively
2	Reduction in blood flow	May affect drug disposition through a number of mechanisms
3	Shunts	Intrahepatic shunts—may account for up to 65% of hepatic blood flow Spontaneous portosystemic shunts and TIPS can significantly modify
4	Changes in protein binding	Impacts delivery of drugs to hepatocytes and can also have an impact on PD response
5	Reduced delivery of oxygen	Oxygen is important for CYP activity
6	Altered transporter expression and function	Hepatocyte uptake as well as efflux into biliary canaliculi can be affected
7	Small bowel CYP activity	TIPS significantly reduces small bowel CYP3A activity
8	Drug-drug interactions	Altered PKs of one compound may have secondary effects on the PKs of coadminstered drugs
9	Impaired renal function	PKs of renally excreted drugs may be profoundly affected in individuals with cirrhosis
10	Altered intestinal absorption	There may be diminished absorption of orally administered drugs and may also influence the PKs of drugs which are bile excreted because of impaired enterohepatic circulation

Abbreviations: CYP, cytochrome P450; TIPS, transjugular intrahepatic portosystemic shunts.