Plasma flow, hepatic

Figure 2 Simulation of the effect of enzyme induction on oral midazolam AUC. Hepatic extraction in the absence of an inducer was set at 0.44. The initial intestinal extraction was varied from 0.0 to 0.9. The inducer was assumed to cause an equivalent change in hepatic and intestinal intrinsic clearance. Mucosal and hepatic plasma flows were assumed to be 240 and 780 mL/min. Simulations were obtained from Eq. (6), assuming an initial intestinal extraction ratio of 0.00, 0.07, 0.27, 0.43, 0.60, and 0.88.

Clemmesen JO, Tygstrup N, Ott P (1998) Hepatic plasma flow estimated according to Pick s principle in patients with hepatic encephalopathy evaluation of indocyanine green and D-sorbitol as test substances. Hepatology 27 . 666-673. 

Zech J, Lange H, Bosch J, et al. Steady-state extrarenal sorbitol clearance as a measure of hepatic plasma flow. Gastroenterology 1988 95 749-759. 

Hepatic blood flow is obtained from the hepatic plasma flow and the packed cell volume. The hepatic plasma flow Fi, is obtained from the expression... 

The extraction ratio for a particular dye tends to vary inversely with the plasma concentration (C9). There is also a tendency for the extraction ratio to vary inversely with the hepatic plasma flow. This has been reported after portacaval shunt operations in man (B43) and after hemorrhage or pyrogen administration in dogs (H7a). 

In a patient or in an experimental animal, the plasma flow to the liver has to be considered in relation to the plasma volume, because only a portion of the plasma circulates through the liver in a single cycle. Thus, increase in plasma volume without change in hepatic plasma flow or in the extraction ratio will on its own slow down the removal of BSP from the circulation. This has been suggested (G4) as a factor operating in late pregnancy, which is characterized by increased dye retention, and possibly it acts also in fainting which reduces BSP uptake (R14). The tendency for the efficiency of parenchymal cells (as reflected in the extraction ratio) to vary inversely with the hepatic plasma flow has been described earlier. 

Assuming complete elimination through hepatic metabolism and renal pathways, the estimated hepatic clearances of R- and S-albuterol after IV injections are 0.40 and 0.036 L/min, respectively [114]. Assuming hepatic plasma flow of 0.8 L/min, these values correspond to hepatic extraction ratios of 0.50 and 0.045 for R- and S-albuterol, respectively. Therefore oral bioavailabilty based on hepatic first-pass metabolism should be 50% and 96% for the active and inactive enantiomers of albuterol, respectively. However, the observed oral bioavailabilities of the R and S enantiomers of albuterol are only 9.4% and 68.7%, indicating a substantial first-pass metabolism in the gastrointestinal tract. This can be attributed to approximately 80% and 30% sulfation of R- and S-albuterol, respectively, in the intestinal wall [112,114]. 

In scenario A (columns 2 and 3) of Table 16.5, where (as shown above) clearance is limited by hepatic plasma flow, a doubling of the fraction of dmg unbound in the plasma has minimal effect on total steady-state drug concentration but results in a near doubling of free steady-state dmg concentration. This increased free concentration will likely increase therapeutic or toxic effect and would require a downward adjustment in dose. 

Qh hepatic plasma flow Ql the infusion rate of a loading intravenous infusion... 

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 the apparent plasma clearance (dose/area under the plasma concentration-time curve, equivalent to true clearance/fraction of dose absorbed) gives an implausibly high value of clearance (e.g., greater than hepatic and renal plasma flow), it is likely the bioavailability is low. However, this could be due to presystemic metabolism in addition to low absorption. 

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... 

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