Hi Josh. Bioavability is the fraction of an administered dose of unchanged drug that reaches the systemic circulation. Even if paracetamol is intensively metabolized in the liver, it doesnt mean that most of the paracetamol must to be transformed. A bigger part of the dose passes through the liver unchanged, because of enzymatic capacity, and will reaches the systemic circulation. Hence 70-90% bioavability depending on the dose.

Thanks very much for your answer Martin, that makes sense. 

Dear Josh,

Martin has explained well enough, so I would like to add few points.

It is important to understand how much of this drug is biotransformed, and how much of it remains unchanged, and why?

First of all, oral bioavailability is dose dependent as Martin has enumerated above. Hepatic metabolism of Paracetamol involves three phases which produces both toxic and non-toxic compounds and several metabolites including NAPQI, one which is responsible for toxicity and liver damage. Paracetamol is extensively metabolized in the liver (majority of the drug is metabolized) and the hepatic cytochrome P450 isoenzyme is involved in its metabolism. Following phase I metabolism, about 5-15% is excreted in the urine as  mercapturic acid or cysteine conjugate1. 

The rate of absorption and availability of this drug also depends on the rate of gastric emptying. Metabolism is impaired in toxic doses and sulphate conjugation which accounts for about 20-30% of paracetamol metabolism, gets saturated. Metabolism is also perhaps altered in chronic alcoholics (although highly debated), which may be one of the reasons for higher bioavailability of its toxic metabolites (also debated).

Furthermore, hepatic diseases may increase its bioavailability (unchanged portion.)

You can refer to this paper which gives a detailed account of APAP metabolism.

1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3709007/  

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014937/

Regards, Sidharta

Thank you very much for the addition Dr Chatterjee, and also thank you for the papers. Very much appreciated! 

In addition to the previous responses, may I add that the bioavailability of a drug which gives an indication of the fraction of an orally administered dose of a drug also depends on the extraction radio of the drug by the liver. Thus, drugs with high extraction ratios tend to exhibit a marked first-pass effect. The extraction ratio, which is the fraction of drug removed during a single transit through the liver, in this case, is a ratio of the hepatic clearance to the hepatic blood flow. It therefore stands to reason that paracetamol must have a low hepatic extraction resulting from a low hepatic clearance hence the high bioavailability despite being subjected to first-pass effect.

 That makes perfect sense Professor Bolaji, thank you very much for your answer! Indeed, it seems the extraction ratio of paracetamol in the rat liver is only 0.07, however this appears to vary with changes in dose. 

http://www.ncbi.nlm.nih.gov/pubmed/2758103

Hi 

Tha attached article may answer your question 

Best Wishes

Dear all, First pass metabolism of paracetamol is inversely related to dose. When given as 1 Gm, about 10-20% is presystemically eliminated (80% is bioavailable). But when dose is smaller then extent of presystemic elimination can be upto 40%.

    But what I wonder is that irrespective of  extent of Ist pass effect, the usual therapeutic doses  given for fever reduction would not change much. The situation may be different for analgesic action requiring higher dose!