# Presentation: 136472

## ACETAMINOPHEN OVERVIEWacetyl-para-aminophenol (APAP)

**John R. Senior, M.D.**
**Senior Scientific Advisor**
**Office of Drug Safety**
**Nonprescription Drugs Advisory Committee Meeting, 19 September 2002**

**Center for Drug Evaluation and Research**** **

## Flight from Pain

## Coal-tar Analgesics

## Aspirin to Acetaminophen (APAP)

- Aspirin **considered a wonder drug for >50 years (1899-1950). . . ***but found to cause gastrointestinal ulcers and bleeding, to cause CNS “salicylism,” altered acid-base balance (respiratory  alkalosis), inhibit cyclooxygenase, Reye’s syndrome in children with viral infections. . .*
- Acetaminophen** approved 1950 and for OTC use about 1959 (proof of efficacy not required) . . . ***did not cause bleeding or GI ulcers, did not cause Reye’s syndrome (noted in 1963, associated with aspirin 1980s) . . . ***............................ *****but, . .***

## Br Med J 1966 (27 Aug); 2 (5512)

**Davidson DGD, Eastham WN. (Edinburgh)         pp 497-9**
**	**** *****Acute liver necrosis following overdose of paracetamol.***
**Thompson JS, Prescott LF.  (Aberdeen)              pp 506-7**
**	**** *****Liver damage and impaired glucose tolerance after paracetamol overdosage.***
**Editorial                                                                   pp 485-6**
***	******Liver necrosis from paracetamol.***

## An Insidious Agent

**After acute ingestion of a large amount (8-20 g in adult) *****may***** (*****or may not*****) experience nausea, sweating, vomiting, drowsiness - - - subsides - **
**“****latent period” of no symptoms for 24-72 hours (*****but a lot of metabolic changes going on*****) - - - **
**nausea, anorexia, vomiting, tender-swollen liver, with ALT and AST in -000s, PT (INR) elevated**
**liver failure: encephalopathy, acidosis, jaundice, 2****o****? renal failure, hypoglycemia, bleeding, . . . death.**

## Acetaminophen (APAP) Conjugates

## J Pharmacol Exp Ther 1973 (Oct); 187Acetaminophen-induced hepatic necrosis

***I.     Role of drug metabolism*****                           pp 185-194****  ****Mitchell JR, Jollow DJ, Potter WZ, Davis DC, Gillette JR, Brodie BB**
***II.   Role of covalent binding ***_***in vivo***_***              *****  pp 195-202**** ****Jollow DJ, Mitchell JR, Potter WZ, Davis DC, Gillette JR, Brodie BB**
***III. Cytochrome P-450-mediated covalent binding ***_***in vitro***_** ****	****	****	****	****	****	****                pp 203-210**** **
**Potter WZ, Davis DC, Mitchell JR, Jollow DJ, Gillette JR, Brodie BB**
**IV. Protective role of glutathione                     pp 211-217****  ****Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB**

## APAP-induced hepatic necrosis

***centrilobular liver necrosis in mice and rats related to drug ****metabolism rate, ****not to plasma levels of drug;***** **
***liver damage severity in mice related to ****covalent binding**** ***_***in vivo***_*** of metabolite to hepatocyte microsomal protein;***
*cytochrome P-450-mediated**** covalent binding of acetaminophen metabolites to cell microsomal protein;*****	**
*glutathione ****depletion worsens, and glutathione addition prevents damage, without affecting metabolism*****                        **

## Acetaminophen Oxidation

- CYP 3A4

## NAPQI Detoxification

**NAPQI**

## Four Lines of Defense

**excretion of unchanged APAP - < 5%**
**glucuronide conjugation - about 55 - 60%**
**conjugation with sulfate - about 30 - 35%**
**mercaptide formation with GSH - about 5%**
**    ****- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -**
**N-acetylcysteine conjugation - *****last chance***

## Moderate, Chronic Overdose

- about 30-50% of hep-toxic cases unintentional
- may have no prodromal symptoms
- doses of 4-8 g/day, after “inducers” dangerous ?
- may develop tolerance (M. Black’s case)
- acetaminophen (APAP) plasma levels not always helpful, and may be too late for effective treatment with Mucomyst (N-acetylcysteine),  - - - - and no time for a liver transplant...

## Factors Affecting Absorption and Metabolism

**dissolution**
**gastric emptying**
**absorption fraction**
**glucuronidation**
**sulfation**
**renal function**
**liver function**
**mercaptides**
**NAPQI formation**
**protein adducts**
**toxic O-reactants**

**solution, capsule, tablet**
**varies up to 9-fold, (-) meals**
**1-3x in uptake, C****max****,AUC, T****1/2**
**(**-**) Gilbert’s, ranitidine**
**(**+**) acetaminophen, estrogens**
**(++) glucuronides, sulfates**
**(++) T****1/2 ****with toxic overdose**
**(**+**) GSH, N-Acys; (-) depletion**
**(**-**) cimetidine, chronic APAP**
**60-fold inter-individual variation**
**“****overdose” for given person**
**reperfusion, ischemia**

## Cytochrome P-450 2E1 Inducers

**alcohol (ethanol)**
**isoniazid**
**acetaminophen**
**aspirin**
**chlorzoxazone**

**other alcohols, acetone**
**retinol (vitamin A)**
**obesity; cigarette smoke**
**clofibrate, ciprofibrate**
**trichlorethylene, pyrazole**

*Also, CYP 1A2 and 3A4 inducers, such as:*

- rifampacin, omeprazole, broiled beef; phenobarbital,
- phenytoin, lovastatin, prednisone, erythromycin, omeprazole,

## foods, nutrients

- AAs, gluc, FAs

- hormones,
- cytokines

- bilirubin

- proteins

- drugs

- alcohol

- OTC
- remedies

- environmental
- chemicals

- dietary supplements,
- food additives,
- herbal products

## Variability of Absorption and Metabolism Among Individuals

**considerable variation at each step**
**absorption, glucuronidation, sulfation, oxidation, GSH conjugation - - - - - - - -  result is 60-fold variation in toxic NAPQI formation among individuals**
**many drug-drug and drug-compound interactions**