Determinants of Drug Disposition in Patients with Cirrhosis†

Abstract

The effects of alterations of the hepatic blood flow, the intrinsic clearance, and the anatomy of the portal circulation on drug disposition were investigated in 53 cirrhotic patients with portal hypertension using indocyanine green (ICG) and lidocaine as model drugs. ICG disposition was studied by sampling from an artery and one hepatic vein following i.v. injection, with determination of systemic and intrinsic clearances and hepatic blood flow. Lidocaine disposition was studied following i.v. and oral administration from peripheral vein disappearance curves, with determination of systemic and intrinsic clearances and systemic availability. The shunted fraction of intestinal blood flow ( f ) was measured from the combined ICG and lidocaine disposition studies. In the 53 patients, systemic clearances of ICG and lidocaine varied widely and were significantly correlated with each other (r = 0.725, p < 0.001). The systemic clearances of both ICG and lidocaine were not related to hepatic blood flow but were significantly correlated to their respective intrinsic clearances (for ICG: r = 0.948, p < 0.001; for lidocaine: r = 0.873, p < 0.001). Lidocaine systemic availability was also found to vary widely from 0.2 to 1.0. In 28 patients, f was ~0 . 1 indicating minimal extrahepatic shunting and in these patients, lidocaine systemic availability was related to its intrinsic clearance (r = -0.717, p c 0.001); in the 25 other patients with significant extrahepatic shunting (f > O.l), the extent of lidocaine systemic availability was related to both intrinsic clearance (r = -0.819, p < 0.001) and extrahepatic shunting (r = 0.913, p < 0.001). It is concluded that, in patients with cirrhosis: (i) the disposition of drugs with intermediate-high hepatic extraction ratios is no longer influenced by hepatic blood flow but becomes limited by intrinsic clearance; and (ii) the decrease of intrinsic clearance plus extrahepatic shunting, when present, are responsible for the increased systemic availability of this type of drug.In recent years, the quantification of the hepatic elimination of drugs has become more physiologically oriented. It is now recognized that, besides the activity of the hepatic drug metabolizing enzymes (intrinsic clearance), hepatic blood flow is also an important determinant of drug clearance (1). These considerations have led to a classification of drug elimination based on their hepatic extraction ratio (2). For drugs with a low hepatic extraction ratio, clearance is determined mainly by the liver's ability to metabolize the drug, i.e., intrinsic clearance, being independent of changes in liver blood flow. ~

Systemic hemodynamics in advanced cirrhosis: Concerns during perioperative period of liver transplantation

“…ICG kinetics is useful to set-up of adequate PVF during LDLT with lower GRWR. Conversely, in deceased-donor LT, although PVF is a major determinant of kICG in the normal liver [32,34,49,51,53] , the kICG value may be affected by damaged hepatocytes due to the longer CIT. The decreased kICG may not indicate only an inadequate PVF in deceased-donor LT because ICG kinetics is dually factorial.…”

“…There is a correlation between ICG clearance and the hepatic uptake ratio assayed by liver scintigraphy [45,46] . ICG kinetics reflect the functional hepatocytes (cell volume) and effective PVF (clearance) [31,[49][50][51][52] , and PVF is a major determinant of kICG in the normal liver [32,34,49,51,53] . The PVF has a large influence on liver regeneration after LT [32,43] , and reversible damage to hepatocytes begins immediately after graft recirculation [32,38,39,43] .…”

Drug dosage recommendations in patients with chronic liver disease

“…When no information was found, the adjustment recommendations were given according to the process defined by Delcò et al (1), based on the method established by Huet et al (11) and Krähenbühl et al (12). This method classifies each drug according to three parameters: hepatic extraction ratio (E H ) -classified in 3 categories (high ≥ 60%, intermediate 30-60% and low ≤ 30%), bioavailability (F) and plasma protein binding (PB) ( Table I).…”

“…This method classifies each drug according to three parameters: hepatic extraction ratio (E H ) -classified in 3 categories (high ≥ 60%, intermediate 30-60% and low ≤ 30%), bioavailability (F) and plasma protein binding (PB) ( Table I). For the drugs with no E H available information, E H was calculated using the formula defined by Westphal et al (11): [E H = (Q 0 x CL syst )/Q H ]. Q 0 values (extra renal drug moiety) and CL syst (systemic or total clearance) were obtained from the literature, assuming a hepatic blood flow (Q H ) of 1.5 L/min.…”

“…In order to have supplementary information to the bibliography, the following parameters were registered for all drugs: E H , bioavailability, plasma protein binding and the corresponding category according to the Huet classification (11).…”