Paracetamol (INN) (pronounced /ˌpærəˈsiːtəmɒl, ˌpærəˈsɛtəmɒl/) or acetaminophen (/əˌsiːtəˈmɪnɵfɨn/ ( listen)) (USAN) is a widely used over-the-counter analgesic (pain reliever) and antipyretic (fever reducer).
It is commonly used for the relief of headaches, and other minor aches and pains, and is a major ingredient in numerous cold and flu remedies. In combination with opioid analgesics, paracetamol can also be used in the management of more severe pain (such as in advanced cancer).[1]
While generally safe for use at recommended doses (1,000 mg per single dose and up to 4,000 mg per day for adults, up to 2,000 mg per day if drinking alcohol),[2] acute overdoses of paracetamol can cause potentially fatal liver damage and, in rare individuals, a normal dose can do the same; the risk is heightened by alcohol consumption. Paracetamol toxicity is the foremost cause of acute liver failure in the Western world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia and New Zealand.[3][4][5][6]
Paracetamol is part of the class of drugs known as "aniline analgesics"; it is the only such drug still in use today.[7] It is the active metabolite of phenacetin, once popular as an analgesic and antipyretic in its own right, but unlike phenacetin and its combinations, paracetamol is not considered to be carcinogenic at therapeutic doses.[8] The words acetaminophen (used in the United States, Canada, Hong Kong, Iran,[9] Colombia and other Latin American countries) and paracetamol (used elsewhere) both come from chemical names for the compound: para-acetylaminophenol and para-acetylaminophenol. In some contexts, it is simply abbreviated as APAP, for N-acetyl-para-aminophenol.
The classification of paracetamol, and the terminology used to refer to it, can cause confusion. It is often classified as a nonsteroidal anti-inflammatory drug (NSAID), but paracetamol has few anti-inflammatory effects in many tissues. However, aspirin, paracetamol and other NSAIDs all act by the same mechanism (inhibition of prostaglandin synthesis) and all show varying levels of analgesic, anti-inflammatory, antipyretic and antiplatelet actions.[10]
วันเสาร์ที่ 24 กรกฎาคม พ.ศ. 2553
History
Acetanilide was the first aniline derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of Antifebrin by A. Cahn and P. Hepp in 1886.[11] But its unacceptable toxic effects, the most alarming being cyanosis due to methemoglobinemia, prompted the search for less toxic aniline derivatives.[7] Harmon Northrop Morse had already synthesized paracetamol at Johns Hopkins University via the reduction of p-nitrophenol with tin in glacial acetic acid in 1877,[12][13] but it was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on patients.[7] In 1893, von Mering published a paper reporting on the clinical results of paracetamol with phenacetin, another aniline derivative.[14] Von Mering claimed that, unlike phenacetin, paracetamol had a slight tendency to produce methemoglobinemia. Paracetamol was then quickly discarded in favor of phenacetin. The sales of phenacetin established Bayer as a leading pharmaceutical company.[15] Overshadowed in part by aspirin, introduced into medicine by Heinrich Dreser in 1899, phenacetin was popular for many decades, particularly in widely advertised over-the-counter "headache mixtures," usually containing phenacetin, an aminopyrine derivative of aspirin, caffeine, and sometimes a barbiturate.[7]
Von Mering's claims remained essentially unchallenged for half a century, until two teams of researchers from the United States analyzed the metabolism of acetanilide and paracetamol.[15] In 1947 David Lester and Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood, and in a subsequent study they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia.[16] In three papers published in the September 1948 issue of the Journal of Pharmacology and Experimental Therapeutics, Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed using more specific methods that paracetamol was the major metabolite of acetanilide in human blood, and established it was just as efficacious an analgesic as its precursor.[17][18][19] They also suggested that methemoglobinemia is produced in humans mainly by another metabolite, phenylhydroxylamine. A followup paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol.[20] This led to a "rediscovery" of paracetamol.[7] It has been suggested that contamination of paracetamol with 4-aminophenol, the substance from which it was synthesized by von Mering, may be the cause for his spurious findings.[15]
Bernard Brodie and Julius Axelrod (pictured) demonstrated that acetanilide and phenacetin are both metabolized to paracetamol, which is a better tolerated analgesic.Paracetamol was first marketed in the United States in 1953 by Sterling-Winthrop Co., which promoted it as preferable to aspirin since it was safe to take for children and people with ulcers.[15] The best known brand today for paracetamol in the United States, Tylenol, was established in 1955 when McNeil Laboratories started selling paracetamol as a pain and fever reliever for children, under the brand name Tylenol Children's Elixir—the word "tylenol" was a contraction of para-acetylaminophenol.[21] In 1956, 500 mg tablets of paracetamol went on sale in the United Kingdom under the trade name Panadol, produced by Frederick Stearns & Co, a subsidiary of Sterling Drug Inc. Panadol was originally available only by prescription, for the relief of pain and fever, and was advertised as being "gentle to the stomach," since other analgesic agents of the time contained aspirin, a known stomach irritant.[citation needed] In 1963, paracetamol was added to the British Pharmacopoeia, and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents.[13] Concerns about paracetamol's safety delayed its widespread acceptance until the 1970s, but in the 1980s paracetamol sales exceeded those of aspirin in many countries, including the United Kingdom. This was accompanied by the commercial demise of phenacetin, blamed as the cause of analgesic nephropathy and hematological toxicity.[7]
The U.S. patent on paracetamol has long expired, and generic versions of the drug are widely available under the Drug Price Competition and Patent Term Restoration Act of 1984, although certain Tylenol preparations were protected until 2007. U.S. patent 6,126,967 filed September 3, 1998 was granted for "Extended release acetaminophen particles".[22]
Von Mering's claims remained essentially unchallenged for half a century, until two teams of researchers from the United States analyzed the metabolism of acetanilide and paracetamol.[15] In 1947 David Lester and Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood, and in a subsequent study they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia.[16] In three papers published in the September 1948 issue of the Journal of Pharmacology and Experimental Therapeutics, Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed using more specific methods that paracetamol was the major metabolite of acetanilide in human blood, and established it was just as efficacious an analgesic as its precursor.[17][18][19] They also suggested that methemoglobinemia is produced in humans mainly by another metabolite, phenylhydroxylamine. A followup paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol.[20] This led to a "rediscovery" of paracetamol.[7] It has been suggested that contamination of paracetamol with 4-aminophenol, the substance from which it was synthesized by von Mering, may be the cause for his spurious findings.[15]
Bernard Brodie and Julius Axelrod (pictured) demonstrated that acetanilide and phenacetin are both metabolized to paracetamol, which is a better tolerated analgesic.Paracetamol was first marketed in the United States in 1953 by Sterling-Winthrop Co., which promoted it as preferable to aspirin since it was safe to take for children and people with ulcers.[15] The best known brand today for paracetamol in the United States, Tylenol, was established in 1955 when McNeil Laboratories started selling paracetamol as a pain and fever reliever for children, under the brand name Tylenol Children's Elixir—the word "tylenol" was a contraction of para-acetylaminophenol.[21] In 1956, 500 mg tablets of paracetamol went on sale in the United Kingdom under the trade name Panadol, produced by Frederick Stearns & Co, a subsidiary of Sterling Drug Inc. Panadol was originally available only by prescription, for the relief of pain and fever, and was advertised as being "gentle to the stomach," since other analgesic agents of the time contained aspirin, a known stomach irritant.[citation needed] In 1963, paracetamol was added to the British Pharmacopoeia, and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents.[13] Concerns about paracetamol's safety delayed its widespread acceptance until the 1970s, but in the 1980s paracetamol sales exceeded those of aspirin in many countries, including the United Kingdom. This was accompanied by the commercial demise of phenacetin, blamed as the cause of analgesic nephropathy and hematological toxicity.[7]
The U.S. patent on paracetamol has long expired, and generic versions of the drug are widely available under the Drug Price Competition and Patent Term Restoration Act of 1984, although certain Tylenol preparations were protected until 2007. U.S. patent 6,126,967 filed September 3, 1998 was granted for "Extended release acetaminophen particles".[22]
Structure and reactivity
Paracetamol consists of a benzene ring core, substituted by one hydroxyl group and the nitrogen atom of an amide group in the para (1,4) pattern.[23] The amide group is acetamide (ethanamide). It is an extensively conjugated system, as the lone pair on the hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, the p orbital on the carbonyl carbon, and the lone pair on the carbonyl oxygen are all conjugated. The presence of two activating groups also make the benzene ring highly reactive toward electrophilic aromatic substitution. As the substituents are ortho,para-directing and para with respect to each other, all positions on the ring are more or less equally activated. The conjugation also greatly reduces the basicity of the oxygens and the nitrogen, while making the hydroxyl acidic through delocalisation of charge developed on the phenoxide anion.
Synthesis
Compared with many other drugs, paracetamol is much easier to synthesize, because it lacks stereocenters. As a result, there is no need to design a stereo-selective synthesis.
Industrial preparation of paracetamol usually proceeds from nitrobenzene.[24] A one-step reductive acetamidation reaction can be mediated by thioacetate.[25]
Paracetamol may be easily prepared in the laboratory by nitrating phenol with sodium nitrate, separating the desired p-nitrophenol from the ortho- byproduct, and reducing the nitro group with sodium borohydride. The resultant p-aminophenol is then acetylated with acetic anhydride.[26] In this reaction, phenol is strongly activating, thus the reaction only requires mild conditions (c.f. the nitration of benzene):
Industrial preparation of paracetamol usually proceeds from nitrobenzene.[24] A one-step reductive acetamidation reaction can be mediated by thioacetate.[25]
Paracetamol may be easily prepared in the laboratory by nitrating phenol with sodium nitrate, separating the desired p-nitrophenol from the ortho- byproduct, and reducing the nitro group with sodium borohydride. The resultant p-aminophenol is then acetylated with acetic anhydride.[26] In this reaction, phenol is strongly activating, thus the reaction only requires mild conditions (c.f. the nitration of benzene):
Available forms
See also: List of paracetamol brand names
Paracetamol is available in a tablet, capsule, liquid suspension, suppository, intravenous, and intramuscular form. The common adult dose is 500 mg to 1000 mg. The recommended maximum daily dose, for adults, is 4000 mg. In recommended doses, paracetamol generally is safe for children and infants, as well as for adults,[28], although rare cases of acute liver injury have been linked to amounts lower than 2.5 grams per day.[29]
Panadol, which is marketed in Africa, Asia, Europe, Central America, and Australasia, is the most widely available brand, sold in over 80 countries. In North America, paracetamol is sold in generic form (usually labeled as acetaminophen) or under a number of trade names, for instance, Tylenol (McNeil-PPC, Inc.), Anacin-3, Tempra, and Datril,. While there is brand named paracetamol available in the UK (e.g. Panadol), unbranded or generic paracetamol is more commonly sold. Acamol, a brand name for paracetamol produced by Teva Pharmaceutical Industries in Israel, is one of the most widely used drugs in that country. In the Philippines, the largest-selling paracetamol brand is Biogesic, manufactured by the drug giant United Laboratories. Biogesic tablet sales reach nearly a billion units each year in the country alone, not including liquid suspension formats. The brand is also available in most of the ASEAN countries where the drug giant has market presence. In Europe, the most common brands of paracetamol are Efferalgan and Doliprane. In India, the most common brand of paracetamol is Crocin manufactured by Glaxo SmithKline Asia. In Bangladesh the most popular brand is Napa manufactured by Beximco Pharma. In China paracetamol is sold over the counter as Duiyixian'anjifenpian (对乙酰氨基酚片).[30] The lack of the english name paracetamol makes it difficult for non-chinese speaking travellers looking to purchase paracetamol.
In some formulations, paracetamol is combined with the opioid codeine, sometimes referred to as co-codamol (BAN). In the United States and Canada, this is marketed under the name of Tylenol #1/2/3/4, which contain 8–10 mg, 15 mg, 30 mg, and 60 mg of codeine, respectively. In the U.S., this combination is available only by prescription, while the lowest-strength preparation is over-the-counter in Canada, and, in other countries, other strengths may be available over the counter. There are generic forms of these combinations as well. In the UK and in many other countries, this combination is marketed under the names of Tylex CD and Panadeine. Other names include Captin, Disprol, Dymadon, Fensum, Hedex, Mexalen, Nofedol, Paralen, Pediapirin, Perfalgan, and Solpadeine. Paracetamol is also combined with other opioids such as dihydrocodeine, referred to as co-dydramol (BAN), oxycodone or hydrocodone, marketed in the U.S. as Percocet and Vicodin, respectively. Another very commonly used analgesic combination includes paracetamol in combination with propoxyphene napsylate, sold under the brand name Darvocet. A combination of paracetamol, codeine, and the calmative doxylamine succinate is marketed as Syndol or Mersyndol.
Paracetamol is commonly used in multi-ingredient preparations for migraine headache, typically including butalbital and paracetamol with or without caffeine, and sometimes containing codeine.
Paracetamol is available in a tablet, capsule, liquid suspension, suppository, intravenous, and intramuscular form. The common adult dose is 500 mg to 1000 mg. The recommended maximum daily dose, for adults, is 4000 mg. In recommended doses, paracetamol generally is safe for children and infants, as well as for adults,[28], although rare cases of acute liver injury have been linked to amounts lower than 2.5 grams per day.[29]
Panadol, which is marketed in Africa, Asia, Europe, Central America, and Australasia, is the most widely available brand, sold in over 80 countries. In North America, paracetamol is sold in generic form (usually labeled as acetaminophen) or under a number of trade names, for instance, Tylenol (McNeil-PPC, Inc.), Anacin-3, Tempra, and Datril,. While there is brand named paracetamol available in the UK (e.g. Panadol), unbranded or generic paracetamol is more commonly sold. Acamol, a brand name for paracetamol produced by Teva Pharmaceutical Industries in Israel, is one of the most widely used drugs in that country. In the Philippines, the largest-selling paracetamol brand is Biogesic, manufactured by the drug giant United Laboratories. Biogesic tablet sales reach nearly a billion units each year in the country alone, not including liquid suspension formats. The brand is also available in most of the ASEAN countries where the drug giant has market presence. In Europe, the most common brands of paracetamol are Efferalgan and Doliprane. In India, the most common brand of paracetamol is Crocin manufactured by Glaxo SmithKline Asia. In Bangladesh the most popular brand is Napa manufactured by Beximco Pharma. In China paracetamol is sold over the counter as Duiyixian'anjifenpian (对乙酰氨基酚片).[30] The lack of the english name paracetamol makes it difficult for non-chinese speaking travellers looking to purchase paracetamol.
In some formulations, paracetamol is combined with the opioid codeine, sometimes referred to as co-codamol (BAN). In the United States and Canada, this is marketed under the name of Tylenol #1/2/3/4, which contain 8–10 mg, 15 mg, 30 mg, and 60 mg of codeine, respectively. In the U.S., this combination is available only by prescription, while the lowest-strength preparation is over-the-counter in Canada, and, in other countries, other strengths may be available over the counter. There are generic forms of these combinations as well. In the UK and in many other countries, this combination is marketed under the names of Tylex CD and Panadeine. Other names include Captin, Disprol, Dymadon, Fensum, Hedex, Mexalen, Nofedol, Paralen, Pediapirin, Perfalgan, and Solpadeine. Paracetamol is also combined with other opioids such as dihydrocodeine, referred to as co-dydramol (BAN), oxycodone or hydrocodone, marketed in the U.S. as Percocet and Vicodin, respectively. Another very commonly used analgesic combination includes paracetamol in combination with propoxyphene napsylate, sold under the brand name Darvocet. A combination of paracetamol, codeine, and the calmative doxylamine succinate is marketed as Syndol or Mersyndol.
Paracetamol is commonly used in multi-ingredient preparations for migraine headache, typically including butalbital and paracetamol with or without caffeine, and sometimes containing codeine.
Mechanism of action
The main mechanism of action of paracetamol is considered to be the inhibition of cyclooxygenase (COX), and recent findings suggest that it is highly selective for COX-2.[32] While it has analgesic and antipyretic properties comparable to those of aspirin or other NSAIDs, its peripheral anti-inflammatory activity is usually limited by several factors, one of which is high level of peroxides present in inflammatory lesions. However, in some circumstances even peripheral anti-inflammatory activity comparable to other NSAIDs can be observed.
Because of its selectivity for COX-2 it does not significantly inhibit the production of the pro-clotting thromboxanes.[32]
AM404—a metabolite of paracetamol
Anandamide—an endogenous cannabinoidThe COX family of enzymes are responsible for the metabolism of arachidonic acid to prostaglandin H2, an unstable molecule which is in turn converted to numerous other pro-inflammatory compounds. Classical anti-inflammatories such as the NSAIDs block this step. Only when appropriately oxidized is the COX enzyme highly active.[33][34]
Paracetamol reduces the oxidized form of the COX enzyme, preventing it from forming pro-inflammatory chemicals.[35][36] This leads to a reduced amount of Prostaglandin E2 in the CNS, thus lowering the hypothalamic set point in the thermoregulatory centre.
Paracetamol also modulates the endogenous cannabinoid system.[37] Paracetamol is metabolized to AM404, a compound with several actions; most important, it inhibits the uptake of the endogenous cannabinoid/vanilloid anandamide by neurons. Anandamide uptake would result in the activation of the main pain receptor (nociceptor) of the body, the TRPV1 (older name: vanilloid receptor). Furthermore, AM404 inhibits sodium channels, as do the anesthetics lidocaine and procaine.[38] Either of these actions by themselves has been shown to reduce pain, and are a possible mechanism for paracetamol. However, it has been demonstrated that, after blocking cannabinoid receptors with synthetic antagonists, paracetamol's analgesic effects are prevented, suggesting its pain-relieving action involves activation of the endogenous cannabinoid system.[39]
The exact mechanisms how COX is inhibited in various circumstances is still subject of discussion. Because of differences in the activity of paracetamol, aspirin and other NSAIDs it has been postulated that further COX variants may exist. A recently discovered COX-1 splice variant termed COX-3 was considered to explain some of the knowledge gap, however newer findings do not support the hypothesis that it plays any significant role in the functioning of paracetamol.[32]
Aspirin is known to inhibit the cyclooxygenase (COX) family of enzymes, and because paracetamol's action is partially similar to aspirin's,[clarification needed] much research has focused on whether paracetamol also inhibits COX. It is now clear that paracetamol acts via at least two pathways.[7][35][40][41]
One theory holds that paracetamol works by inhibiting the COX-3 isoform of the COX family of enzymes. When expressed in dogs, this enzyme shares a strong similarity to the other COX enzymes, produces pro-inflammatory chemicals, and is selectively inhibited by paracetamol.[42] However, some research has suggested that in humans and mice, the COX-3 enzyme is without inflammatory action.[40] Another possibility is that paracetamol blocks cyclooxygenase (as in aspirin), but that is in an inflammatory environment where the concentration of peroxides is high, and the high oxidation state of paracetamol prevents its actions. This would mean that paracetamol has no direct effect at the site of inflammation, but instead acts in the CNS where the environment is not oxidative, to reduce temperature, etc.[42] The exact mechanism by which paracetamol is believed to affect COX-3 is disputed.
Because of its selectivity for COX-2 it does not significantly inhibit the production of the pro-clotting thromboxanes.[32]
AM404—a metabolite of paracetamol
Anandamide—an endogenous cannabinoidThe COX family of enzymes are responsible for the metabolism of arachidonic acid to prostaglandin H2, an unstable molecule which is in turn converted to numerous other pro-inflammatory compounds. Classical anti-inflammatories such as the NSAIDs block this step. Only when appropriately oxidized is the COX enzyme highly active.[33][34]
Paracetamol reduces the oxidized form of the COX enzyme, preventing it from forming pro-inflammatory chemicals.[35][36] This leads to a reduced amount of Prostaglandin E2 in the CNS, thus lowering the hypothalamic set point in the thermoregulatory centre.
Paracetamol also modulates the endogenous cannabinoid system.[37] Paracetamol is metabolized to AM404, a compound with several actions; most important, it inhibits the uptake of the endogenous cannabinoid/vanilloid anandamide by neurons. Anandamide uptake would result in the activation of the main pain receptor (nociceptor) of the body, the TRPV1 (older name: vanilloid receptor). Furthermore, AM404 inhibits sodium channels, as do the anesthetics lidocaine and procaine.[38] Either of these actions by themselves has been shown to reduce pain, and are a possible mechanism for paracetamol. However, it has been demonstrated that, after blocking cannabinoid receptors with synthetic antagonists, paracetamol's analgesic effects are prevented, suggesting its pain-relieving action involves activation of the endogenous cannabinoid system.[39]
The exact mechanisms how COX is inhibited in various circumstances is still subject of discussion. Because of differences in the activity of paracetamol, aspirin and other NSAIDs it has been postulated that further COX variants may exist. A recently discovered COX-1 splice variant termed COX-3 was considered to explain some of the knowledge gap, however newer findings do not support the hypothesis that it plays any significant role in the functioning of paracetamol.[32]
Aspirin is known to inhibit the cyclooxygenase (COX) family of enzymes, and because paracetamol's action is partially similar to aspirin's,[clarification needed] much research has focused on whether paracetamol also inhibits COX. It is now clear that paracetamol acts via at least two pathways.[7][35][40][41]
One theory holds that paracetamol works by inhibiting the COX-3 isoform of the COX family of enzymes. When expressed in dogs, this enzyme shares a strong similarity to the other COX enzymes, produces pro-inflammatory chemicals, and is selectively inhibited by paracetamol.[42] However, some research has suggested that in humans and mice, the COX-3 enzyme is without inflammatory action.[40] Another possibility is that paracetamol blocks cyclooxygenase (as in aspirin), but that is in an inflammatory environment where the concentration of peroxides is high, and the high oxidation state of paracetamol prevents its actions. This would mean that paracetamol has no direct effect at the site of inflammation, but instead acts in the CNS where the environment is not oxidative, to reduce temperature, etc.[42] The exact mechanism by which paracetamol is believed to affect COX-3 is disputed.
Metabolism
Paracetamol is metabolised primarily in the liver, into non-toxic products. Three metabolic pathways are notable:
Glucuronidation is believed to account for 40% to two-thirds of the metabolism of paracetamol.[43]
Sulfation (sulfate conjugation) may account for 20–40%.[43]
N-hydroxylation and rearrangement, then GSH conjugation, accounts for less than 15%. The hepatic cytochrome P450 enzyme system metabolizes paracetamol, forming a minor yet significant alkylating metabolite known as NAPQI (N-acetyl-p-benzo-quinone imine).[44] NAPQI is then irreversibly conjugated with the sulfhydryl groups of glutathione.[44]
All three pathways yield final products that are inactive, non-toxic, and eventually excreted by the kidneys. In the third pathway, however, the intermediate product NAPQI is toxic. NAPQI is primarily responsible for the toxic effects of paracetamol; this constitutes an excellent example of toxication.
Production of NAPQI is due primarily to two isoenzymes of cytochrome P450: CYP2E1 and CYP1A2. The P450 gene is highly polymorphic, however, and individual differences in paracetamol toxicity are believed to be due to a third isoenzyme, CYP2D6. Genetic polymorphisms in CYP2D6 may contribute to significantly different rates of production of NAPQI. Furthermore, individuals can be classified as "extensive", "ultrarapid", and "poor" metabolizers (producers of NAPQI), depending on their levels of CYP2D6 expression. Although CYP2D6 metabolises paracetamol into NAPQI to a lesser extent than other P450 enzymes, its activity may contribute to paracetamol toxicity in extensive and ultrarapid metabolisers, and when paracetamol is taken at very large doses.[45] At usual doses, NAPQI is quickly detoxified by conjugation.[44] Following overdose, and possibly also in extensive and ultrarapid metabolizers, this detoxification pathway becomes saturated and consequently NAPQI accumulates.
Glucuronidation is believed to account for 40% to two-thirds of the metabolism of paracetamol.[43]
Sulfation (sulfate conjugation) may account for 20–40%.[43]
N-hydroxylation and rearrangement, then GSH conjugation, accounts for less than 15%. The hepatic cytochrome P450 enzyme system metabolizes paracetamol, forming a minor yet significant alkylating metabolite known as NAPQI (N-acetyl-p-benzo-quinone imine).[44] NAPQI is then irreversibly conjugated with the sulfhydryl groups of glutathione.[44]
All three pathways yield final products that are inactive, non-toxic, and eventually excreted by the kidneys. In the third pathway, however, the intermediate product NAPQI is toxic. NAPQI is primarily responsible for the toxic effects of paracetamol; this constitutes an excellent example of toxication.
Production of NAPQI is due primarily to two isoenzymes of cytochrome P450: CYP2E1 and CYP1A2. The P450 gene is highly polymorphic, however, and individual differences in paracetamol toxicity are believed to be due to a third isoenzyme, CYP2D6. Genetic polymorphisms in CYP2D6 may contribute to significantly different rates of production of NAPQI. Furthermore, individuals can be classified as "extensive", "ultrarapid", and "poor" metabolizers (producers of NAPQI), depending on their levels of CYP2D6 expression. Although CYP2D6 metabolises paracetamol into NAPQI to a lesser extent than other P450 enzymes, its activity may contribute to paracetamol toxicity in extensive and ultrarapid metabolisers, and when paracetamol is taken at very large doses.[45] At usual doses, NAPQI is quickly detoxified by conjugation.[44] Following overdose, and possibly also in extensive and ultrarapid metabolizers, this detoxification pathway becomes saturated and consequently NAPQI accumulates.
สมัครสมาชิก:
บทความ (Atom)