ANATOMY AND PHYSIOLOGY OF THE LIVER
The liver is the major organ responsible for drug metabolism. However, intestinal tissues, lung, kidney, and skin also contain appreciable amounts of biotransformation enzymes.
The liver is both a synthesizing and an excreting organ. The basic unit of liver is the liver lobule, which contains parenchymal cells, a network of interconnected lymph and blood vessels. The liver consists of large right and left lobes that merge in the middle. The liver is perfused by blood from the hepatic artery; in addition, the large hepatic portal vein that collects blood from various segments of the GI tract also perfuses the liver. The hepatic artery carries oxygen to the liver and accounts for about 25% of the liver blood supply. The hepatic portal vein carries nutrients to the liver and accounts for about 75% of liver blood flow. The terminal branches of the hepatic artery and portal vein fuse within the liver and mix with the large vascular capillaries known as sinusoids. Blood leaves the liver via the hepatic vein, which empties into the vena cava. The liver also secretes bile acids within the liver lobes, which flow through a network of channels and eventually empty into the common bile duct. The common bile duct drains bile and biliary excretion products from both lobes into the gallbladder.
Sinusoids are blood vessels that form a large reservoir of blood, facilitating drug and nutrient removal before the blood enters the general circulation. The sinusoids are lined with endothelial cells, or Kupffer cells. Kupffer cells are phagocytic tissue macrophages that are part of the reticuloendothelial system (RES). Kupffer cells engulf worn-out red blood cells and foreign material.
Drug metabolism in the liver has been shown to be flow and site dependent. Some enzymes are reached only when blood flow travels from a given direction. The quantity of enzyme involved in metabolizing drug is not uniform throughout the liver. Consequently, changes in blood flow can greatly affect the fraction of drug metabolized. Clinically, hepatic diseases, such as cirrhosis, can cause tissue fibrosis, necrosis, and hepatic shunt, resulting in changing blood flow and changing bioavailability of drugs. For this reason, because of genetic differences in enzyme levels among different subjects and environmental factors, the half-lives of drugs eliminated by drug metabolism are generally very variable.
Hepatic clearance may be defined as the volume of blood that perfuses the liver and is cleared of drug per unit of time.
Total body clearance is composed of all the clearances in the body:
Where
Ø Cl T is total body clearance,
Ø Cl nr is nonrenal clearance (often equated with hepatic clearance, Cl h), and
Ø Cl r is renal clearance.
Hepatic clearance (Cl h) is also equal to total body clearance (Cl T) minus renal clearance (Cl R) assuming no other organ metabolism, as shown by Equation
FIRST-PASS EFFECTS
Definition
The first-pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation.
Explanation
For some drugs, the route of administration affects the metabolic rate of the compound. For example, a drug given parenterally, transdermally, or by inhalation may distribute within the body prior to metabolism by the liver. In contrast, drugs given orally are normally absorbed in the duodenal segment of the small intestine and transported via the mesenteric vessels to the hepatic portal vein and then to the liver before entering the systemic circulation. Drugs that are highly metabolized by the liver or by the intestinal mucosal cells demonstrate poor systemic availability when given orally. This rapid metabolism of an orally administered drug before reaching the general circulation is termed first-pass effect or presystemic elimination.
Evidence of First-Pass Effects
First-pass effects may be suspected when there is a lack of parent (or intact) drug in the systemic circulation after oral administration. In such a case, the AUC for a drug given orally is less than the AUC for the same dose of drug given intravenously. From experimental findings in animals, first-pass effects may be assumed if the intact drug appears in a cannulated hepatic portal vein but not in general circulation.
For an orally administered drug that is chemically stable in the gastrointestinal tract and is 100% systemically absorbed (F = 1), the area under the plasma drug concentration curve, AUC∞ 0, oral, should be the same when the same drug dose is given intravenously, AUC∞ 0, IV. Therefore, the absolute bioavailability (F) may reveal evidence of drug being removed by the liver due to first-pass effects as follows:
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For drugs that undergo first-pass effects AUC∞0, oral is smaller than AUC∞0, IV and F < 1. Drugs such as propranolol, morphine, and nitroglycerin have F values less than 1 because these drugs undergo significant first-pass effects.
Liver Extraction Ratio
Because there are many other reasons for a drug to have a reduced F value, the extent of first-pass effects is not very precisely measured from the F value. The liver extraction ratio (ER) provides a direct measurement of drug removal from the liver after oral administration of a drug.
Where
Ø Ca is the drug concentration in the blood entering the liver and
Ø Cv is the drug concentration leaving the liver.
Because Ca is usually greater than Cv, ER is usually less than 1. For example, for propranolol, ER or [E] is about 0.7—that is, about 70% of the drug is actually removed by the liver before it is available for general distribution to the body. By contrast, if the drug is injected intravenously, most of the drug would be distributed before reaching the liver, and less of the drug would be metabolized.
Liver ER provides a measurement of liver extraction of a drug orally administered. Unfortunately, sampling of drug from the hepatic portal vein and artery is difficult and performed mainly in animals. Animal ER values may be quite different from those in humans. The following relationship between bioavailability and liver extraction enables a rough estimate of the extent of liver extraction:
Where
Ø F is the fraction of bioavailable drug,
Ø ER is the drug fraction extracted by the liver, and
Ø F″ is the fraction of drug removed by nonhepatic process.
If F″ is assumed to be negligible, that is, there is no loss of drug due to chemical degradation, gut metabolism, and incomplete absorption, ER may be estimated from
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After substitution of Equation 1 into Equation 2,
FACTORS AFFECTING THE ER VALUE
ER is a rough estimation of liver extraction for a drug. Many other factors may alter this estimation:
Ø The size of the dose,
Ø The formulation of the drug, and
Ø The pathophysiologic condition of the patient.
IMPORTANCE OF ER VALUE
Liver ER provides valuable information in determining the oral dose of a drug when the intravenous dose is known. For example, propranolol requires a much higher oral dose compared to an IV dose to produce equivalent therapeutic blood levels, because of oral drug extraction by the liver. Because liver extraction is affected by blood flow to the liver, dosing of drug with extensive liver metabolism may produce erratic plasma drug levels. Formulation of this drug into an oral dosage form requires extensive, careful testing.
ESTIMATION OF REDUCED BIOAVAILABILITY DUE TO FIRST PASS METABOLISM AND VARIABLE BLOOD FLOW
Blood flow to the liver plays an important role in the amount of drug metabolized after oral administration. Changes in blood flow to the liver may substantially alter the percentage of drug metabolized and therefore alter the percentage of bioavailable drug. The relationship between blood flow, hepatic clearance, and percent of drug bioavailable is
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Where
Ø Cl h is the hepatic clearance of the drug and
Ø Q is the effective hepatic blood flow.
Ø F' is the bioavailability factor obtained from estimates of liver blood flow and hepatic clearance,
Ø ER represents the extraction ratio,
This equation provides a reasonable approach for evaluating the reduced bioavailability due to first-pass effect. The usual effective hepatic blood flow is 1.5 L/min, but it may vary from 1 to 2 L/min depending on diet, food intake, physical activity or drug intake.
Example
For the drug propoxyphene hydrochloride, F' has been calculated from hepatic clearance (990 mL/min) and an assumed liver blood flow of 1.53 L/min:
The results, showing that 35% of the drug is systemically absorbed after liver extraction, are reasonable compared with the experimental values for propranolol.
SIGNIFICANCE OF FIRST PASS METABOLISM
- Presystemic elimination or first-pass effect is a very important consideration for drugs that have a high extraction ratio.
Drugs with low extraction ratios, such as theophylline, have very little presystemic elimination, as demonstrated by complete systemic absorption after oral administration.
Drugs with high extraction ratios have poor bioavailability when given orally. Therefore, the oral dose must be higher than the intravenous dose to achieve the same therapeutic response.
In some cases, oral administration of a drug with high presystemic elimination, such as nitroglycerin, may be impractical due to very poor oral bioavailability, and thus a sublingual, transdermal, or nasal route of administration may be preferred.
- If an oral drug product has slow dissolution characteristics or release rate, then more of the drug will be subject to first-pass effect compared to doses of drug given in a more bioavailable form (such as a solution). In addition, drugs with high presystemic elimination tend to demonstrate more variability in drug bioavailability between and within individuals. Finally, the quantity and quality of the metabolites formed may vary according to the route of drug administration, which may be clinically important if one or more of the metabolites has pharmacologic or toxic activity.
- The route of administration of the drug may be changed. For example, nitroglycerin may be given sublingually or topically, and xylocaine may be given parenterally to avoid the first-pass effects. Another way to overcome first-pass effects is to either enlarge the dose or change the drug product to a more rapidly absorbable dosage form. In either case, a large amount of drug is presented rapidly to the liver, and some of the drug will reach the general circulation in the intact state.
- Although Equation 3 seems to provide a convenient way of estimating the effect of liver blood flow on bioavailability, this estimation is actually more complicated. A change in liver blood flow may alter hepatic clearance and F'. A large blood flow may deliver enough drug to the liver to alter the rate of metabolism. In contrast, a small blood flow may decrease the delivery of drug to the liver and become the rate-limiting step for metabolism. The hepatic clearance of a drug is usually calculated from plasma drug data rather than whole-blood data. Significant nonlinearity may be the result of drug equilibration due to partitioning into the red blood cells.
| Hepatic and Renal Extraction Ratios of Representative Drugs | ||||||
| Extraction Ratios | ||||||
| Low (<0.3) | | Intermediate (0.3–0.7) | High (>0.7) | | ||
| Hepatic Extraction | ||||||
| Warfarin | | Aspirin | Morphine | | ||
| Salicylic acid | | Quinidine | Nitroglycerin | | ||
| Erythromycin | | Desipramine | Propoxyphene | | ||
| Isoniazid | | Nortriptyline | Propranolol | | ||
| Phenytoin | | | Verapamil | | ||
HEPATIC CLEARANCE OF A PROTEIN-BOUND DRUG: RESTRICTIVE AND NONRESTRICTIVE CLEARANCE FROM BINDING
It is generally assumed that protein-bound drugs are not easily metabolized (restrictive clearance), while free (unbound) drugs are subject to metabolism. Protein-bound drugs do not easily diffuse through cell membranes, while free drugs can reach the site of the mixed-function oxidase enzymes easily. Therefore, an increase in the free drug concentration in the blood will make more drug available for hepatic extraction. The concept is discussed under restrictive and nonrestrictive clearance of protein-bound drugs.
Most drugs are restrictively cleared, for example, diazepam, quinidine, tolbutamide, and warfarin. The clearance of these drugs is proportional to the fraction of unbound drug (f u). However, some drugs, such as propranolol, morphine, and verapamil, are nonrestrictively extracted by the liver regardless of drug bound to protein or free. Kinetically, a drug is nonrestrictively cleared if its hepatic extraction ratio (ER) is greater than the fraction of free drug (f u), and the rate of drug clearance is unchanged when the drug is displaced from binding. Mechanistically, the protein binding of a drug is a reversible process and for a nonrestrictively bound drug, the free drug gets "stripped" from the protein during the process of drug metabolism. The elimination half-life of a nonrestrictively cleared drug is not significantly affected by a change in the degree of protein binding. This is an analogous situation to a protein-bound drug that is actively secreted by the kidney.
For a drug with restrictive clearance, the relationship of blood flow, intrinsic clearance, and protein binding is
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f u is the fraction of drug unbound in the blood and
Cl' int is the intrinsic clearance of free drug.
Equation 5 is derived by substituting f uCl' int for Cl int in Equation (b) i.e. in
From Equation 5, when Cl' int is very small in comparison to hepatic blood flow (ie, Q > Cl' int), then Equation (c) reduces to Equation (d).
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As shown in Equation (d), a change in Cl' int or f u will cause a proportional change in Cl h for drugs with protein binding.
In the case where Cl' int for a drug is very large in comparison to flow (Cl' int >> Q), Equation 6 reduces to Equation 7.
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Thus, for drugs with a very high Cl'int, Clh is dependent on hepatic blood flow, and independent of protein binding.
For restrictively cleared drugs, change in binding generally alters drug clearance. For a drug with low hepatic extraction ratio and low plasma binding, clearance will increase, but not significantly, when the drug is displaced from binding. For a drug highly bound to plasma proteins (more than 90%), a displacement from these binding sites will significantly increase the free concentration of the drug, and clearance (both hepatic and renal clearance) will increase. There are some drugs that are exceptional and show a paradoxical increase in hepatic clearance despite an increase in protein binding. In one case, increased binding to AAG (α, acid glycoprotein) was found to concentrate drug in the liver, leading to an increased rate of metabolism because the drug was nonrestrictively cleared in the liver.
EFFECT OF CHANGING PROTEIN BINDING ON HEPATIC CLEARANCE
The effect of protein binding on hepatic clearance is often difficult to quantitate precisely, because it is not always known whether the bound drug is restrictively or nonrestrictively cleared. For example, animal tissue levels of imipramine, a nonrestrictively cleared drug, was shown to change as the degree of plasma protein binding changes. As discussed, drug protein binding is not a factor in hepatic clearance for drugs that have high extraction ratios. These drugs are considered to be flow limited. In contrast, drugs that have low extraction ratios may be affected by plasma protein binding depending on the fraction of drug bound. For a drug that has a low extraction ratio and is less than 75–80% bound, small changes in protein binding will not produce significant changes in hepatic clearance. These drugs are considered capacity-limited, binding-insensitive drugs. Drugs that are highly bound to plasma protein but with low extraction ratios are considered capacity limited and binding sensitive, because a small displacement in the protein binding of these drugs will cause a very large increase in the free drug concentration. These drugs are good examples of restrictively cleared drugs. A large increase in free drug concentration will cause an increase in the rate of drug metabolism, resulting in an overall increase in hepatic clearance.
REFERENCES
Ø Applied biopharmaceutics and pharmacokinetics by Leon Sharjel
Ø Text book of biopharmaceutics and clinical pharmacokinetics by Sarfaraz Niazi
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