Hepatic blood clearance

Pang, K.S. and Rowland, M., Hepatic clearance of drugs, 1. Theoretical considerations of a well-stirred model and a parallel tube model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic blood clearance, J. Pharmacokinet. Biopharm., 1977, 5, 625-653. 

A special case for reduced bioavailabilty results from first-pass extraction that sometimes might be subjected to saturable Michaelis-Menten absorption kinetics. The lower the hepatic drug clearance is (Clhep) in relation to liver blood flow (Ql), or the faster the drug absorption rate constant (Ka), and the higher the dose (D) are, the more bioavailable is the drug (F). 

Thus, if the hepatic clearance for a drug is largely relative to the hepatic blood flow, the extent of availability for this drug will be low when it is given by a route that yields first-pass effects. The decrease in availability is a function of only the anatomical site... 

T5. Tygstrup, N., and Winkler, K., Galactose blood clearance as a measure of hepatic blood flow. Clin. Sci. 17, 1-9 (1958). 

If reduced plasma clearance of BSP were related to anesthetic induced alterations in hepatic blood flow it should be evident early in the course of the intoxication when these types of effects would be most pronounced. We have reported that significant plasma retention of BSP in rainbow trout occurred only within the first 24 h after treatment with MCB... 

An implication of the high degree of hepatic extraction is that clearance of nicotine should be dependent on liver blood flow. Thus, physiological events, such as meals, posture, exercise, or drugs perturbing hepatic blood flow, are predicted to affect the rate of nicotine metabolism. Meals consumed during a steady state infusion of nicotine result in a consistent decline in nicotine concentrations, the maximal effect seen 30-60 min after the end of a meal (Gries et al. 1996 Lee et al. 1989). Hepatic blood flow increases about 30% and nicotine clearance increases about 40% after a meal. 

The estimation of systemic clearance together with this value gives valuable information about the behaviour of a drug. High clearance drugs with values approaching hepatic blood flow will indicate hepatic extraction (metabolism) as a reason for low bioavailability. In contrast poor absorption will probably be the problem in low clearance drugs which show low bioavailabilities. 

The equation can be solved for intrinsic clearance (Clj) based upon systemic clearance (Clj) obtained after i.v. administration and hepatic blood flow (Q) in the test species. Intrinsic clearance in man can then be estimated based upon relative in vitro microsomal stabibty and the equation solved to provide an estimate for human systemic clearance. Hence this approach combines aUometry (by considering differences in organ blood flow) and species-specific differences in metabolic clearance. 

In addition to hepatic blood flow and function, ICG plasma clearance is also a useful prognostic factor for selecting patients for hepatectomy [1311. A majority of model systems developed for continuous hepatic function monitoring rely on the clearance profile of indocyanine green (ICG), which is the primary focus of this section. 

Pharmacokinetics When administered intravenously, ICG rapidly binds to plasma proteins and is exclusively cleared by the liver, and subsequently secreted into the bile [8]. This forms the basis of the use of ICG for monitoring hepatic blood flow and function. Two pharmacokinetics models, a monoexponential decay, which describes the initial rapid clearance of ICG with a half-life of about 3 minutes (Eq. (1)) and a bi-exponential model, which incorporates the secondary phase clearance with a longer half-life (Eq. (2)), describe total clearance of ICG from plasma [ 132]. For real-time measurements by continuous organ function monitoring, the mono-exponential decay is preferred. 

Plasma protein-bound drugs that are substrates for transport carriers can be cleared from blood at great velocity, e.g., p-aminohippurate by the renal tubule and sulfobromophthalein by the liver. Clearance rates of these substances can be used to determine renal or hepatic blood flow. 

Flumazenil is a highly extracted drug. Clearance of flumazenil occurs primarily by hepatic metabolism and is dependent on hepatic blood flow. In healthy volunteers, total clearance ranges from 0.7 to 1.3 L/h/kg, with less than 1% of the administered dose eliminated unchanged in urine. Elimination of drug is essentially complete within 72 hours, with 90% to 95% appearing in urine and 5% to 10% in feces. 

Drug/Food interactions Ingestion of food during an IV infusion of flumazenil results in a 50% increase in flumazenil clearance, most likely due to the increased hepatic blood flow that accompanies a meal. 

Buprenorphine is metabolized by the liver mediated by cytochrome P450 3A4, and its clearance is related to hepatic blood flow. Plasma protein binding is about 96%. The mean elimination half-life from plasma is 37 hours. 

What makes prediction of drug elimination complex are the multiple possible pathways involved which explain why there is no simple in vitro clearance assay which predicts in vivo clearance. Because oxidative metabolism plays a major role in drug elimination, microsomal clearance assays are often used as a first line screen with the assumption that if clearance is high in this in vitro assay it is likely to be high in vivo. This assumption is often, but not always true because, for example, plasma protein binding can limit the rate of in vivo metabolism. However, compounds which have a low clearance in hepatic microsomes can be cleared in vivo via other mechanisms (phase II metabolism, plasmatic errzymes). Occasionally, elimination is limited by hepatic blood flow, and other processes like biliary excretion are then involved. The conclusion is that the value of in vitro assays needs to be established for each chemical series before it can be used for compound optimization. 

Lignocaine s clearance by the liver is flow dependent. In heart failure cardiac output may be very low and therefore hepatic blood flow through both the hepatic artery and the portal venous system is also low. This meant a lower extraction of the drug from the blood and accumulation of lignocaine until the high plasma concentration produced the central nervous system toxicity. 

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