Paracetamol absorption

RC Heading, J Nimmo, LF Prescott, P Tothill. The dependence of paracetamol absorption on the rate of gastric emptying. Br J Pharmacol 47 415-421, 1973. 

Gramatte, T., Richter, K., Paracetamol absorption from different sites in the human small intestine, Br. J. Clin. Pharmacol. 1994, 37, 608-611. 

Opioids such as diamorphine, pethidine, and pentazocine strongly inhibit gastric emptying and greatly reduce the absorption rate of paracetamol. Codeine, however, has no significant effect on paracetamol absorption. Morphine and diamorphine have been shown to reduce the absorption of antiarrhyth-mics such as mexiletine in patients with myocardial infarction. 

Although the toxicological significance has yet to be studied, age-related differences in the absorption of foreign compounds are demonstrable. Neonatal and geriatric human subjects have low gastric acid secretion, and consequently the absorption of some foreign compounds may be altered. Thus in the neonate, penicillin absorption is enhanced, whereas paracetamol absorption is decreased. 

Nimmo I, Heading RC, Tothill P, Prescott LF. Pharmacological modification of gastric emptying Effects of propantheline and metclopromide on paracetamol absorption. Br Med J 1973 1 587-9. 

Intravenous metoclopramide 10 mg increased the peak plasma levels of a single 1.5-g dose of paracetamol by 64% in 5 healthy subjects (slow absorbers of paracetamol), and increased its rate of absorption (peak levels reached in 48 minutes instead of 120 minutes), but the total amount absorbed remained virtually unaltered. Oral metoclopramide also increases the rate of paracetamol absorption, probably because the rate of gastric emptying is increased. Similarly, the speed of absorption of paracetamol may also be increased by domperidone. This interaction is exploited in Paramax (a proprietary oral preparation containing both paracetamol and metoclopramide) to increase the effectiveness and onset of analgesia for the treatment of migraine. This is obviously an advantageous interaction in this situation. 

Propantheline reduced the rate, but not the extent, of paracetamol absorption. This would be expected to reduce the rate of onset of analgesia. Other antimuscarinic drugs that delay gastric emptying would be expected to interact similarly. In one case, the diphenhydramine component of a paracetamol product delayed paracetamol absorption after an overdose, and complicated the evaluation of the risk of toxicity. 

Erythromycin accelerates gastric emptying and increases paracetamol absorption but this does not appear to result in a clinically significant interaction. 

In a study in healthy subjects, intravenous erythromycin 0.75 to 3 mg/kg accelerated gastric emptying in a dose-dependent manner and increased paracetamol absorption. However, another study found that erythromycin 200 mg intravenously, given to promote gastrointestinal motility, did not alter the pharmacokinetics of an extended-release oral dose of paracetamol. A further study in 7 healthy subjects reported that the pharmacokinetics of a single 1-g oral dose of paracetamol were not significantly... 

Food slows the rate of absorption of paracetamol, but the overall bioavailability is not usually affected. However, in some individuals food may delay and reduce peak paracetamol-plasma levels. A high fat meal may slightly reduce the extent of paracetamol absorption and certain foods, such as cabbage and brussels sprouts, may affect the metabolism of paracetamol, but this is unlikely to be clinically significant. 

Clark R Holdsworth CD, Rees MR, Howlett PJ. The effect on paracetamol absorption of stimulation and blockade of p-adrenoceptors. BrJ Clin Pharmacol (1980) 10,555-9. 

The bioavailability of paracetamol 1 g (using salivaiy paracetamol levels over 4 hours as a measure of paracetamol absorption) was found to be unchanged in 6 healthy subjects given sucralfate... 

Rowbotham DJ, Parnacott S, Nimmo WS. No effect of cisapride on paracetamol absorption after oral simultaneous administration. EurJClin Pharmacol (1992) 42, 235-6. 

The other peaks demonstrate the power of NMR to identify and quantitate all the components of a sample. This is very important for die phannaceutical industry. Most of the peaks, including a small one accidentally underlying the methyl resonance of paracetamol, arise from stearic acid, which is connnonly added to paracetamol tablets to aid absorption. The integrals show diat it is present in a molar proportion of about 2%. The broader peak at 3.4 ppm is from water, present because no attempt was made to dry the sample. Such peaks may be identified either by adding fiirther amounts of the suspected substance, or by the more fiindamental methods to be outlined below. If the sample were less concentrated, then it would also be... 

Anadin Extra contains paracetamol, aspirin and caffeine, the latter being a mild stimulant that increases the absorption and activity of the analgesics, paracetamol and aspirin. 

Examples of the type of peaks which arise due to absorption by the O-H group can be seen in the IR spectrum of 4 -hydroxyacetophenone (Figure 3.3), in which there are broad O-H peaks centered on 3304 cm" (non-hydrogen bonded) and 3158 cm" (due to hydrogen bonding), and paracetamol (Figure 3.4), in which there is an O-H absorption at 3161 cm". ... 

The IR spectrum of aniline (Figure 3.7) shows a typical N-H absorption pattern for a primary amine, with stretches at 3432, 3355 and 3214 cm , while that of paracetamol (Figure 3.4) shows the single stretch observed for a secondary amide at 3325 cm and we can also see the contrast between this sharp peak and the much broader O-H at 3161 cm . The spectrum of benzocaine (Figure 3.8) also shows the three bands at 3423, 3342 and 3221 cm which characterize a primary amine. 

In the spectrum of paracetamol (Figure 3.4), identify the C=O absorption for the secondary amide group. 

Finally, in this region are the N H bending vibrations (1640-1550 cm ), which will have corresponding stretching vibrations between 3600 and 3200 cm, These absorptions are often difficult to distinguish from C—C vibrations. The N-H vibration of the secondary amide paracetamol is probably responsible for the absorption at 1564 cm (Figure 3.4), while that of aniline (Figure 3.7) may be partly responsible (in addition to the CC stretch) for the peak at 1620 cm. ... 

Supportive treatment is essential, and stomach wash and multiple doses of charcoal may be used. Acetylcysteine or methionine can be given to prevent absorption of charcoal. Antidote treatment must be started after suspected paracetamol ingestion and continued depending on blood levels of paracetamol. Appropriate care must be taken in patients receiving enzyme-inducing drugs.79,80... 

Gangwal and Sharma [16] described a simultaneous spectrophotometric method for the determination of mefenamic acid and paracetamol in their combined dosage forms based on the native UV absorbance maxima of mefenamic acid and paracetamol in 0.02 M NaOH. Mefenamic acid exhibits two absorption maxima at 285 nm and 333 nm, while paracetamol has one absorbance maxima at 257 nm. In a separate study, the same group [17] also reported a spectrophotometric procedure for mefenamic acid and paracetamol in two component tablet formulations. The method is based on the two-wavelength method of calculation. The difference in absorbances at 217 nm and 285 nm was used for determination of mefenamic acid, and the difference in absorbances at 257 nm and 308.8 nm was used for the determination of paracetamol. Beer s law is obeyed by both the drugs within the concentration ranges employed for analysis. The method has been statistically validated, and was found to be satisfactory. 

Good examples are paracetamol and BHT. Paracetamol has a typical sharp peak at 3330 cm-1 for the N-H stretch and then a rounded absorption for the hydrogen-bonded O-H stretch from 3300 down to 3000 cm-1 in the gap between the N-H and C-H stretches. By contrast, BHT has a sharp absorption at 3600 cm-1 as the two large and roughly spherical f-butyl groups prevent the normal H bond from forming. 

We can use the N-H and O-H absorptions to rule out an alternative isomeric structure for paracetamol an ester with an NH2 group instead of an amide with NH and OH, This structure must be wrong as it would give two similar sharp peaks at about 3300 cm-1 instead of the one sharp and one broad peak actually observed. 

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