Hepatic clearance

This chapter answers parts from Section B(iv) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "describe the mechanisms of drug clearance and metabolism". The liver is responsible for the bulk of biotransformation reactions, and the college has asked about it twice, in Question 20 from the first paper of 2016 and Question 15 from the second paper of 2019.  In broad brushstrokes the candidates were expected to outline its role in drug pharmacokinetics. A specific question would be easier; for something like this one would really need to come with a prefabricated answer structure. The objective of these notes is to help generate such a structure.

The official college textbook of pharmacokinetics (Birkett et al, 2009) has an entire chapter devoted to this topic (How drugs are cleared by the liver; Ch.4, p.38) and the level of detailed offered there is entirely satisfactory for the purposes of answering written exam questions about hepatic clearance. For that matter, first pass metabolism is handled well by Chapter 5 (ibid). In terms of the published peer-reviewed material, good examples include vintage articles such as the 1975 piece by Wilkinson and Shand, or the more recent and crit-care-related McKindley et al (1998).  Specifically for first pass metabolism, Pond and Tozer (1984) are an excellent resource.

In summary:

• The two major determinants of hepatic clearance are hepatic extraction ratio and hepatic blood flow
• Hepatic extraction ratio is the fraction of the drug entering the liver in the blood which is irreversibly removed (extracted) during one pass of the blood through the liver.
• The hepatic extraction ratio is determined largely by the free (unbound) fraction of the drug and by the intrinsic clearance rate
• Intrinsic clearance is the intrinsic ability of the liver to remove (metabolise) the drug in absence of restrictions imposed on drug delivery to the liver cell by blood flow or protein binding.
• The effect of liver blood flow on hepatic clearance depends on the hepatic extraction ratio of the drug.
• With increasing hepatic blood flow, hepatic extration ratio will decrease for all drugs.
• For drugs with low intrinsic clearance:
  • Hepatic extraction ratio will drop more rapidly with increasing hepatic blood flow
  • Hepatic clearance will not increase significantly with increasing blood flow
• For drugs with high intrinsic clearance:
  • Hepatic clearance will increase in a fairly linear fashion, in proportion to hepatic blood flow
  • Increasing the intrinsic clearance will have diminishing effect on total hepatic clearance 

Hepatic clearance

The two major determinants of hepatic clearance are the efficiency of drug removal from the blood and the efficiency of blood delivery to the liver. The former is described by the hepatic extraction ratio, and the latter is simply the blood flow to the liver. Thus, the equation below is basically "flow times extraction ratio".

The hepatic extraction ratio here is represented by everything beyond the "×" symbol. 

Hepatic extraction ratio

Birkett et a (2009) offers us the official definition of the hepatic extraction ratio:

"Hepatic extraction ratio ... is the fraction of the drug entering the liver in the blood which is irreversibly removed (extracted) during one pass of the blood through the liver".

As usual, other definitions are available.

An important factor which affects the hepatic extraction ratio is protein binding. Hepatocytes only have access to the free unbound fraction of the drug and the hepatic extraction ratio equation reflects that fact:

The other major variable in this equation is intrinsic clearance (Cl_int). 

Intrinsic clearance

Birkett et a (2009) defines intrinsic clearance as follows:

"[Intrinsic clearance] is the intrinsic ability of the liver to remove (metabolise) the drug in absence of restrictions imposed on drug delivery to the liver cell by blood flow or protein binding"

In other words, the intrinsic clearance is the raw metabolising power of the hepatocytes. If the intrinsic clearance for a drug is very high, its metabolism by the liver is limited by hepatic blood flow (i.e. the liver can only crack as many molecules as are presented to it). If the drug has an extremely low intrinsic clearance, hepatic blood flow will have minimal influence on its metabolic rate (the hepatocytes won't work any harder no matter how much drug you present to them).

Intrinsic clearance is described by the following equation:

The V_max is the maximal rate of enzymatic reaction which is possible for that specific drug-enzyme interaction. If it is presented with unlimited supplies of substrate, the enzyme system would become saturated and drug elimination would become zero-order. The V_max is the reaction rate at this  plateau of activity.

The K_m is the Michaelis-Menten constant which describes the affinity of the enzyme for its substrate. It is the concentration required to achieve 50% of the maximum reaction rate.

The effects of changes in intrinsic clearance and blood flow on drug metabolism

In summary, with increasing hepatic blood flow, hepatic extration ratio will decrease for all drugs.

• For drugs with low intrinsic clearance:
  • Hepatic extraction ratio will drop more rapidly with increasing hepatic blood flow
  • Hepatic clearance will not increase significantly with increasing blood flow
• For drugs with high intrinsic clearance:
  • Hepatic clearance will increase in a fairly linear fashion, in proportion to hepatic blood flow
  • Increasing the intrinsic clearance will have diminishing effect on total hepatic clearance 

The rate of blood flow to the liver determines the rate of drug delivery to the liver, and therefore the net hepatic clearance of the drug depends on blood flow. If 100% of the drug is cleared from the blood during a single pass, the drug's hepatic clearance is completely dependent on the blood flow, and will fluctuate depending on the cardiac output and other haemodynamic variables.

The relationship between blood flow and intrinsic clearance is best described by this classic diagram, reinterpreted here from the excellent aneskey.com.

The relationship works like this. With a low intrinsic clearance rate, the extraction ratio drops dramatically whenever the hepatic blood flow increases. This basically means that increasing the hepatic blood flow has minimal positive effect on the total clearance of the drug.

With a high intrinsic clearance, the hepatic metabolism is highly effective at removing the drug from the circulation. Increased blood flow will increase the delivery of the substrate to the enzyme system, and the enzyme system will cope admirably. As a result, the extraction ratio drops minimally, and the hepatic clearance of the drug increases in proportion to the increased blood flow. The higher the intrinsic clearance, the more linear this relationship.

The same intrinsic clearance graphs can be plotted on a graph comparing hepatic clearance to hepatic blood flow.

Notice how beyond a certain point increasing intrinsic clearance does not significantly change the total hepatic clearance as blood flow increases. As Birkett puts it, it is difficult to improve on the efficiency of an already efficient system.

Examples of drugs with different hepatic clearance profiles

In case one is ever called upon to provide examples of drugs with high and low extraction ratios, here is one we prepared earlier.

High hepatic extraction ratio Glyceryl trinitrate Verapamil Propanolol Lignocaine Morphine Ketamine Metoprolol Propofol

Low hepatic extraction ratio Diazepam Lorazepam Warfarin Phenytoin Carbamazepine Theophylline Methadone Rocuronium

The drugs with a high extraction ratio will have their total hepatic clearance highly dependent on hepatic blood flow, and in low flow states their metabolism will suffer. Drugs with a low extraction ratio will be limited mainly by the uselessness of hepatic enzymes, and their metabolism will be largely unchanged in low flow states. Generally, one can guess when a  drug is going to have a low hepatic extraction ratio from the fact their pharmacokinetics are either non-linear or zero-order, reflecting the fact that their metabolic enzymes reach their saturation point (V_max) at a low concentration.

Examples of disease states which alter hepatic blood flow

McKindley et al (1998) offer an excellent review of different disease states common to critical care which alter hepatic blood flow and make major changes to the total body clearance of drugs with a high hepatic extraction ratio. In summary:

• Early sepsis: hepatic arterial blood flow increased dramatically (it doubled) during this early hyperdynamic stage of sepsis in sheep who had their caecums ligated and punctured.
• Late sepsis: hepatic blood flow decreases significantly, as does blood flow to all other organs
• Haemorrhagic shock: hepatic blood flow decreases significantly with haemorrhage and hypovolaema; in hypovolaemic dogs the half-life of midazolam was increased by 150% (it's a molecule with intermediate intrinsic clearance).
• Cardiogenic shock: obviously, the decreased cardiac output and widepread splanchinc vasoconstriction leads to significantly decreased hepatic blood flow

The authors of the abovelinked article have an excellent table of how the commonly used ICU drugs affect hepatic blood flow; this table is reproduced below:

Notably, vasodilators and inodilators lead to increased cardiac output and therefore increased hepatic blood flow, whereas vasoconstrictors like noradrenaline and phenylephrine lead to decreased hepatic blood flow.

First pass clearance

First pass clearance is distinct from hepatic clearance. The definition given by Birkett et al satisfies the "short and memorable" criteria for exam revision purposes:

"First pass clearance ... is the extent to which a drug is removed by the liver during its first passage in the portal blood through the liver to the systemic circulation"

First pass clearance has an important relationship with hepatic extraction ratio, i.e. it relies significantly on that variable. If a drug has a low hepatic extraction ratio, it will also have low first pass clearance. If the hepatic enzymes are highly efficient, the hepatic extraction ratio will be high and the fraction of drug escaping first pass metabolism will be low.

In summary:

• First pass clearance is a combination of:
  • Metabolism by gut bacteria
  • Metabolism by intestinal brush border enzymes
  • Metabolism in the portal blood
  • Metabolism by liver enzymes 
• For drugs with low hepatic extraction ratio, first pass clearance will be low
• For drugs with high hepatic extraction ratio, first pass clearance will be high

There is a considerable difference in the effect of hepatic enzyme inhibition and activation on the bioavailability of drugs with high and low extraction ratios. In short:

• For drugs with high hepatic extraction ratio, a small change in liver enzyme activity will lead to only a small change in first pass metabolism, but a large clinically significant change in bioavailability
• For drugs with low hepatic extraction ratio, a change in liver enzyme activity will lead to a proportional change in first pass metabolism, which may not change the bioavailability by a clinically significant degree.

Consider a drug that is completely absorbed and undergoes 95% clearance by first pass metabolism, making its systemic bioavailability 5%. With enzyme inhibition, a minor 5% drop in hepatic enzyme activity will result in a doubling of systemic bioavailability (to 10%), which could represent a toxic concentration for drugs with a narrow therapeutic index. Enzyme activation, increasing the activity by just 2.5%, will halve the bioavailability

Alternatively, consider a drug that undergoes only 5% clearance by first pass metabolism. If liver enzymes are induced and their capacity doubles, the first pass clearance increases to 10%, decreasing the bioavailability of this drug from 95% to only 90% of the administered dose. Hepatic enzyme function would have to increase by ten times in order to achieve a halving of the bioavailability for this drug. On the other hand, with hepatic enzyme inhibition, where the enzyme activity is decreased ten times, will decrease first pass clearance from 5% to 0.5%, and the bioavailability of the drug will increase from 95% to 99.5%.  

In short, when comparing drugs with high and low hepatic extraction ratios, changes in hepatic enzyme function will clearly have the greatest effect for the first pass clearance of drugs with a high hepatic extraction ratio, per unit of enzyme function change. Still, Stoelting insists that 

""If the hepatic extraction ratio is <0.3, only a small fraction of the drug delivered to the liver is removed per unit of time. As a result, an excess of drug is available for hepatic elimination mechanisms, and changes in hepatic blood flow will not greatly influence hepatic clearance. A decrease in protein binding or an increase in enzyme activity, as associated with enzyme induction, will greatly increase hepatic clearance of a drug with a low hepatic extraction ratio."

Also, it is important to point out that the first pass through the liver is not the only sort of first pass clearance which could take place. For instance, the reason those phenylephrine-containing decongestant tablets are so useless is the high rate of first pass metabolism by MAO at the intestinal brush border 

In summary, the following are major clinical implications of first pass clearance:

• Drugs with a high first pass clearance will have greater individual variability in plasma concentration.
• Drugs with a high first pass clearance will have a greater difference between the oral and IV doses
• The oral bioavailablility of drugs with a high first pass clearance will be more affected by drug interactions which change enzyme kinetics
• In the presence of portosystemic shunts, some portal blood bypasses first pass clearance and therefore bioavailability of drugs with a high first pass clearance will be increased
• Giving IV and oral doses of drugs with high first-pass metabolism and nonzero renal clearance will generate different quantities of metabolites (oral administration will produce more), which is important if these metabolites are toxic

Birkett et al give verapamil as a stereotypic drug with high individual variability due to high first pass clearance and individual differences in enzyme kinetics. Pond and Tozer (1984) offer a longer list, an abridged version of which is reproduced below:

• Amitriptyline
• Dihydroergotamine
• 5-fluorouracil
• Hydralazine
• Metoprolo
• Morphine
• Neostigmine
• Nifedipine
• Propranolol

There are two main pharmacokinetic models for first pass metabolism, used to predict steady state drug concentration in the context of regular maintenance dosing. These two models are the 'well-stirred' model (Rowland et al, 1973) and the 'parallel tube' model (Brauer, 1963). Ahmad et al  (1983) wrote a good comparison of these models. In short, the tube model predicts that steady-state drug concentration increases with increasing hepatic blood flow, whereas the well-stirred model predicts that it will stay the same. The well-mixed model regards the liver as a well-mixed compartment where enzyme and substrate are homogeneously mixed and equally available to one another. The parallel tube model views the liver as a series of tubes where enzyme is equally available along the length of the tube, but where the substrate concentration decreases as it travels through the tube. Birkett et al (2009) omit any discussion of these, likely because from the exam revision standpoint they can be dismissed as esoteric minutiae. It would suffice to say that the well-mixed model appears to be the one which everybody has defaulted to, and all the other models have little merit (Benet et al, 2017).

Influence of liver function on pharmacokinetics

So, the liver metabolises drugs. However there are several other ways in which liver function and dysfunction influences pharmacokinetics. There are some good articles about this in the literature, most notably Rodighiero (2012)

The effects of changes in synthetic function

• The liver synthesises plasma proteins; plasma protein binding influences the volume of distribution
• Low plasma protein levels lead to raised free drug levels (the free fraction increases)
• This process is therefore synergistic with the concurrent decrease in liver blood flow and hepatic extraction ratio
• The liver synthesises plasma esterases and peptidases; these metabolise certaindrugs
• Significant liver disease can result in prolonged clearance of drugs which are susceptible to these enzymes (eg. suxamethonium)

The effect of changes in secretory function

• Drugs and metabolites which rely on biliary excretion will be retained, and may require dose adjustment
• Drugs which enjoy enterohepatic recirculation may have decreased halflives due to failure of recirculation
• High bilirubin levels may result in the displacement of drugs from albumin as it competes for binding sites 
• Decreased secretion of bile may result in malabsorption 

The effects of portal hypertension on pharmacokinetics

• Portal venous hypertension leads to shunting of portal venous blood into the systemic circulation
• This has the effect of decreasing first pass metabolism