Hepatic blood/plasma flow

The total clearance is the sum of the clearances in all organs. If the clearance of drug from blood/plas-ma approaches the blood/plasma flow through the liver, this indicates that the drug is likely to undergo hepatic first-pass removal. An estimate of Clp... 

KS Pang, M Rowland. Hepatic clearance of drugs. I. 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 drug clearance. J Pharmacokin Biopharm 5/6 625-653, 1977. 

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... 

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. 

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. 

Reduced hepatic mass reduced hepatic blood flow. Often decreased metabolizing isoenzyme activity. PseudocapiUar-ization of hepatic sinusoids Reduced renal plasma flow reduced glomerular filtration rate, altered tubular transport function... 

Cardiac failure may also affect metabolism by altering hepatic blood flow. However, even after heart attack without hypotension or cardiac failure, metabolism may be affected. For example, the plasma clearance of lidocaine is reduced in this situation. Other diseases such as those, which affect hormone levels hyper-or hypothyroidism, lack of or excess growth hormone, and diabetes can alter the metabolism of foreign compounds. 

The average plasma clearance is 600 to 980 ml/min with a blood clearance of 1.0 to 1.6 L/min, which is close to hepatic blood flow. This indicates that the rate of metabolism of THC is dependent on hepatic blood flow. Approximately 70% of a dose of THC is excreted in the urine (30%) and... 

After 40 years of age, liver mass decreases at a rate of approximately 1 percent per year, in addition to a reduction in blood flow (40-50 percent), resulting in a diminished ability to metabolize drugs. However, since hepatic drug metabolism varies widely among individuals, there are no absolute age-related alterations in this regard. Cardiac output also decreases by approximately 1 percent per year beginning at 30 years of age and contributes to the decrease in hepatic blood flow. Glomerular filtration rate, renal plasma flow, and tubular secretory capacity also become reduced. 

It has been demonstrated that hepatic extraction ratio (ER) is also influenced by blood flow. A number of mathematical models have been proposed to explain this observation, but the simplest model, and the one that is easiest to apply to clinical practice, is the well stirred or venous equilibrium model (Equation 5.3). This model relates hepatic clearance to hepatic blood flow (Q), the fraction of drug concentration that is unbound in plasma (fu) and the intrinsic clearance of the unbound drug (Clyint) [1]. Intrinsic clearance represents the maximum clearance of drug in the absence of any restrictions caused by blood flow, binding or access to the metabolising enzymes. The model states that ... 

BETA-BLOCKERS LIDOCAINE 1. Risk of bradycardia (occasionally severe), 1 BP and heart failure with intravenous lidocaine 2. Risk of lidocaine toxicity due to t plasma concentrations of lidocaine, particularly with propranolol and nadolol 3. t plasma concentrations of propranolol and possibly some other beta-blockers 1. Additive negative inotropic and chronotropic effects 2. Uncertain, but possibly a combination of beta-blocker-induced reduction in hepatic blood flow (due to 1 cardiac output) and inhibition of metabolism of lidocaine 3. Attributed to inhibition of metabolism by lidocaine 1. Monitor PR, BP and ECG closely watch for development of heart failure when intravenous lidocaine is administered to patients on beta-blockers 2. Watch for lidocaine toxicity 3. Be aware. Regional anaesthetics should be used cautiously in patients with bradycardia. Beta-blockers could cause dangerous hypertension due to stimulation of alpha-receptors if epinephrine is used with focal anaesthetic... 

PROPANOLOL MAPROTILINE Cases of T plasma levels of maprotiline with propanolol Uncertain at present. Postulated that maprotiline metabolism 1 by alterations in hepatic blood flow Monitor plasma levels of maprotiline when initiating beta-blocker therapy... 

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