Paracetamol Chloramphenicol

Benzoic acids substituted with a basic side chain also are also of interest as pro-moieties whose physicochemical properties and rates of enzymatic hydrolysis can readily be modulated. A number of drugs have been converted to prodrugs with this type of pro-moiety, e.g., hydrocortisone, prednisolone, acyclovir, chloramphenicol, and paracetamol [148] [149], These prodrugs appear well suited as parenteral formulations, being water-soluble, stable in slightly acidic solution, and readily hydrolyzed enzymatically. As examples, we consider here the hydrolysis in human plasma of a number of (aminomethyl)ben-zoates of metronidazole (8.109-8.115, Sect. 8.5.5.1, Table 8.9) [138], These prodrugs are very rapidly activated, which may be beneficial for parenteral administration. However, this type of pro-moiety may be cleaved too rapidly after oral administration to be of interest for poorly absorbed drugs. 

Drugs must also be considered as foreign compounds, and an essential part of drug treatment is to understand how they are removed from the body after their work is completed. Glucuronide formation is the most important of so-called phase II metabolism reactions. Aspirin, paracetamol, morphine, and chloramphenicol are examples of drugs excreted as glucuronides. 

Electrochemical detectors can be used in the oxidative mode for a wide range of drugs, including cannabinoids, haloperidol, morphine, paracetamol, phenothiazines, salicylic acid, and tricyclic antidepressants. Operation in the reductive mode is more difficult as dissolved oxygen must be removed from the eluent (K. Bratin et al, J. liq. Chromat., 1981,, 1777-1795). Reductive applications include chloramphenicol and benzodiazepines. 

These are prepared by rapid solidification of the fused melt of two components that show complete liquid miscibility but negligible solid-solid solubility. Thermodynamically, such a system is an intimately blended physical mixture of its two crystalline components. Thus, the X-ray diffraction pattern of a eutectic constitutes an additive composite of the two components. A phase diagram of a two-component system is shown in Fig. 1. Examples of this type include phenacetin-phenobarbital, chloramphenicol-urea, griseofulvin-sucdnic acid, paracetamol-urea, and the dispersions of giiseofulvin and tolbutamide in polyethylene glycol-(PEG-2000).[ ... 

Paracetamol altered the pharmacokinetics of chloramphenicol in some studies but not in others. 

In six adults the half-life of chloramphenicol, 1 g intravenously was increased from 3.3 to 15 hours by paracetamol 100 mg intravenously (72). 

In contrast, in five children aged 2.5-5 years paracetamol 50 mg/kg/day for several days significantly lowered the Cmax of chloramphenicol, increased its apparent volume of distribution and clearance, and slightly shortened its half-life (73). 

Buchanan N, Moodley GP. Interaction between chloramphenicol and paracetamol. BMJ 1979 2(6185) 307-8. 

Siegers, C.R Moller-Hartmann, W. Cholestyramine as an antidote against paracetamol-inducedhepato-and nephrotoxicity in the rat. Toxicol.Lett., 1989, 47, 179-184 [rat urine extracted metabolites] Lam, S. Malikin, G. An improved micro-scale protein precipitation procedure for HPLC assay of therapeutic drugs in serum. J.Liq.Chromatogr., 1989, 12, 1851-1872 [serum also amiodarone, aspirin, caffeine, chloramphenicol, flecainide, pentobarbital, procainamide, pyrimethamine, quinidine, theophylline, tocainide, trazodone fluorescence detection UV detection]... 

Although there is limited evidence to surest that paracetamol may affect chloramphenicol pharmacokinetics its validity has been criticised. Evidence of a clinically relevant interaction appears to be lacking. 

Three studies report alterations in the pharmacokinetics of chloramphenicol hy paracetamol. The first was conducted in 6 adults in intensive care after an ohservafion thaf fhe half-life of chloramphenicol was prolonged hy paracefamol in children wifh kwashiorkor. The addition of 100 mg of intravenous paracetamol inereased the half-life of chloramphenicol in the adults from 3.25 to 15 hours. Ttowever, this study has been criticised because of potential errors in the method used to calculate the half-life, the unusual doses and routes of administration used, and because the pharmacokinetics of the chloramphenicol with and without paracetamol were calculated at different times after the administration of chloramphenicol. ft has also been pointed out that malnutrition (e.g. kwashiorkor) can increase the elimination rate and AUC of chloramphenicol independently of paraeetamol. ... 

The seeond study demonstrated a different interaetion, in that the elear-ance of chloramphenicol was increased and the half-life reduced This study has also been criticised as it does not account for the fact that chloramphenicol clearance increases over the duration of a treatment course, which suggests that the changes seen in the pharmacokinetics of chloramphenicol may be independent of the paracetamol. The authors later admit this as a possibility. The third study found no differences in the pharmacokinetics of chloramphenicol after the first dose, but at steady state, the AUC and peak serum levels of chloramphenicol were lower in children who also received paracetamol. ... 

Three other studies have failed to confirm the existence of a pharmacokinetic interaction between chloramphenicol and paracetamol. 

Rajpurohit R, Krishnaswamy K. Lack of effect of paracetamol on the phaimacokinetics of chloramphenicol in adult human subjects. Indian JPhatm (1984) 16,124-8. 

Stein CM, Thornhill DP, Neill P, NyazemaNZ. Lack of effect of paracetamol on the pharmacokinetics of chloramphenicol. BrJ Clin Pharmacol (1989) 27, 262-4. 

Examples of substances that are prone to hydrolysis are acetylsalicylic acid, ampicillin, barbiturates, chloramphenicol, chlordiazepoxide, cocaine, corticosteroid phosphate or succinate esters, proteins, folinic acid, indomethacin, local anaesthetics, paracetamol (acetaminophen), pilocarpine, tropa alkaloids (atropine, scopolamine), xylomethazoline and the antimicrobial preservatives methyl and propyl parahydroxybenzoate. In the field of oncology, melphalan and bendamustine hydrochloride are highly susceptable to hydrolysis with a shelf life of 1.5 h for melphalan and 3.5 h for bendamustine at room temperature. 

Vitamins, lactose, glucose, sodium glutamate, Urotropin, antibiotics (oxytetracycline), paracetamol, pancreatin powder, ASA Aminosalicyclic acid, bacitracin, blood plasma, blood serum, methicillin salts, culture media, dextran, enzymes, gamma-globulin, hormones, streptomycin, iron dextran, lysine, casein hydrolysate, penidllin, serum hydrolysate, penicillin, serum hydrolysate, tetracycline vitamins, oleandomydn, chloramphenicol sucdnate salts... 

---