Prodrug Of Acetaminophen Research Articles

Role of Human Orphan Esterases in Drug-induced Toxicity

Esterases hydrolyze compounds containing ester, amide, and thioester bonds, causing prodrug activation or detoxification. Among esterases, carboxylesterases have been studied in depth due to their ability to hydrolyze a variety of drugs. However, there are several drugs for which the involved esterase(s) is unknown. We found that flutamide, phenacetin, rifamycins (rifampicin, rifabutin, and rifapentine), and indiplon are hydrolyzed by arylacetamide deacetylase (AADAC), which is highly expressed in human liver and gastrointestinal tissues. Flutamide hydrolysis is considered associated with hepatotoxicity. Phenacetin, a prodrug of acetaminophen, was withdrawn due to side effects such as methemoglobinemia and renal failure. It was demonstrated in vitro and in vivo using mice that AADAC is responsible for phenacetin hydrolysis, which leads to methemoglobinemia. In addition, it was shown that AADAC-mediated hydrolysis attenuates the cytotoxicity of rifamycins. Thus AADAC plays critical roles in drug-induced toxicity. Another orphan esterase, α/β hydrolase domain containing 10 (ABHD10), was found responsible for deglucuronidation of acyl-glucuronides including mycophenolic acid acyl-glucuronide and probenecid acyl-glucuronide. Because acyl-glucuronides appear associated with toxicity, ABHD10 would function as a detoxification enzyme. The roles of orphan esterases are becoming increasingly understood. Further studies will facilitate our knowledge of the pharmacologic and toxicological significance of orphan esterases in drug therapy.

Pharmacological screening of glycine amino acid prodrug of acetaminophen.

Objective:To develop an amino acid prodrug of acetaminophen with comparable therapeutic profile and less hepatotoxicity than acetaminophen.Materials and Methods:Acetaminophen prodrug was synthesized by esterification between the carboxyl group of amino acid glycine and hydroxyl group of acetaminophen. Analgesic, antipyretic, ulcer healing, and hepatotoxic activities were performed on Wistar rats in this study.Results:Prodrug showed a 44% inhibition in writhings as compared to 53.3% of acetaminophen. Acetaminophen also offered highest antipyretic activity. Prodrug showed gastroprotective and hepatoprotective effects as it reduced the gastric lesions by 32.1% (P < 0.01) and significantly prevented the rise in liver enzymes (serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase and bilirubin). The most notable effect of prodrug was in preventing the depletion of hepatic glutathione (GSH), which is reduced by acetaminophen.Conclusion:Prodrug showed hepatoprotective and gastroprotective effects, although the therapeutic efficacy was compromised. Prodrug was successful in preventing a decrease in GSH, thereby exhibiting promising results in the field of prodrug designing to avoid the toxic effects of acetaminophen.

Acetaminophen (Paracetamol)

Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles (hq@palliativedrugs.com).

Development of acetaminophen proline prodrug

In this research work, proline ester prodrug of acetaminophen (Pro-APAP) was synthesized and evaluated for its stability in PBS buffer at various pH and Caco-2 cell homogenate. The Pro-APAP is more stable at lower pH than higher pH, with half-life of 120 min in PBS buffer at pH 2.0, half-life of 65 min at pH 5.0, and half life of 3.5 min at pH 7.4, respectively. The half-life of Pro-APAP in Caco-2 cell homogenate is about 1 min, much shorter than the half-life in PBS buffer at pH 7.4, indicating enzymes in the cell homogenate contribute to the hydrolysis of the ester bond. Carboxypeptidase A was incubated with Pro-APAP at pH 7.4 with half-life of 3.8 min which is very close to the half life in buffer itself. This clearly indicates carboxypeptidase A is not one of the enzymes contributing to the hydrolysis of the prodrug. Physicochemical characteristics such as melting point and stability of newly synthesized prodrug were determined by MDSC technique.

I.V. acetaminophen pharmacokinetics in neonates after multiple doses

BackgroundPharmacokinetics of an i.v. prodrug of acetaminophen (propacetamol) in neonates after repeat dosing are reported, with scant data for i.v. acetaminophen formulation. MethodsNeonates from an intensive care unit received 6-hourly prn i.v. acetaminophen dosed according to postmenstrual age (PMA): 28–32 weeks, 10 mg kg−1; 32–36 weeks, 12.5 mg kg−1; and ≥36 weeks, 15 mg kg−1. A maximum of five blood samples for assay and liver function tests (LFTs) were collected. A one-compartment linear disposition model (zero-order input; first-order elimination) was used to describe time–concentration profiles using population modelling (NONMEM). ResultsFifty neonates, median (range) PMA 38.6 (32–45) weeks, mean (sd) weight 2.9 (0.7) kg, received a mean of 15 doses over a median 4 days with 189 serum acetaminophen and 231 LFT measurements. Standardized population parameter estimates for a term neonate were clearance (CL) 5.24 (CV 30.5%) litre h−1 70 kg−1 and volume of distribution (V) 76 (29.6%) litre 70 kg−1. CL increased with PMA from 4.4 litre h−1 70 kg−1 at 34 weeks to 6.3 litre h−1 70 kg−1 at 46 weeks. The presence of unconjugated hyperbilirubinaemia was associated with reduced CL: 150 μmol litre−1 associated with 40% CL reduction. Acetaminophen concentrations between 10 and 23 mg litre−1 at steady state are predicted after 15 mg kg−1 6-hourly for a neonate of PMA 40 weeks. Hepatic enzyme analysis of daily samples changed significantly for one patient whose alanine aminotransferase concentration tripled. ConclusionsThe parameter estimates are similar to those described for propacetamol. There was no evidence of hepatotoxicity. Unconjugated hyperbilirubinaemia impacts upon CL, dictating dose reduction.

Comparison of Parecoxib and Proparacetamol in Endoscopic Nasal Surgery Patients

PurposeThe aim of the study was to compare the efficacy of parecoxib for postoperative analgesia after endoscopic turbinate and sinus surgery with the prodrug of acetaminophen, proparacetamol.Materials and MethodsFifty American Society of Anesthesiology (ASA) physical status I-II patients, receiving functional endoscopic sinus surgery (FESS) and endoscopic turbinectomy, were investigated in a prospective, randomized, double-blind manner. After local infiltration with 1% mepivacaine, patients were randomly allocated to receive intravenous (IV) administration of either 40 mg of parecoxib (n = 25) or 2 g of proparacetamol (n = 25) 15 min before discontinuation of total IV anaesthesia with propofol and remifentanil. A blinded observer recorded the incidence and severity of pain at admission to the post anaesthesia care unit (PACU) at 10, 20, and 30 min after PACU admission, and every 1 h thereafter for the first 6 postoperative h.ResultsThe area under the curve of VAS (AUCVAS) calculated during the study period was 669 (28 - 1901) cm·min in the proparacetamol group and 635 (26 - 1413) cm·min in the parecoxib group (p = 0.34). Rescue morphine analgesia was required by 14 patients (56%) in the proparacetamol group and 12 patients (48%) in the parecoxib (p ≥ 0.05), while mean morphine consumption was 5 - 3.5 mg and 5 - 2.0 mg in the proparacetamol groups and parecoxib, respectively (p ≥ 0.05). No differences in the incidence of side effects were recorded between the 2 groups. Patient satisfaction was similarly high in both groups, and all patients were uneventfully discharged 24 h after surgery.ConclusionIn patients undergoing endoscopic nasal surgery, prior infiltration with local anaesthetics, parecoxib administered before discontinuing general anaesthetic, is not superior to proparacetamol in treating early postoperative pain.

This Month in Anesthesiology

This Month in Anesthesiology

Morphine-sparing effect of nefopam by continuous intravenous injection after abdominal surgery by laparotomy

Morphine-sparing effect of nefopam by continuous intravenous injection after abdominal surgery by laparotomy

5-HT receptor subtypes involved in the spinal antinociceptive effect of acetaminophen in rats

The present study was designed to investigate which subtype of spinal 5-HT receptors were involved in acetaminophen-induced antinociception using the paw-pressure test. Propacetamol (prodrug of acetaminophen, 400 mg/kg, injected intravenously, corresponding to 200 mg/kg of acetaminophen) produced a significant antinociceptive effect in this test. This effect was at least partially inhibited by intrathecal (i.t.) pretreatment with the 5-HT 1B (penbutolol), 5-HT 2A (ketanserin), 5-HT 2C (mesulergine) receptor antagonists, but not by the 5-HT 1A ( N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride, WAY 100635) and 5-HT 3 (granisetron) receptor antagonists. This profile was very close to that obtained recently with 5-HT, which suggests an implication of 5-HT in the spinal antinociceptive effect of acetaminophen. These results, the lack of binding of acetaminophen to 5-HT receptors and the increase of central 5-HT levels induced by this drug suggest that acetaminophen-induced antinociception could be indirectly mediated by 5-HT.

Intravenous Administration of Propacetamol Reduces Morphine Consumption After Spinal Fusion Surgery

We sought to determine the analgesic efficacy, opioid-sparing effects, and tolerability of propacetamol, an injectable prodrug of acetaminophen, in combination with morphine administered by patient-controlled analgesia (PCA) after spinal fusion surgery. Forty-two patients undergoing spinal stabilization surgery were randomized into two groups, which were given either an IV placebo or an IV injection of 2 g propacetamol every 6 h for 3 days after surgery. The postoperative opioid analgesic requirement was assessed with a PCA device used to self-administer morphine. Pain relief was evaluated by a visual analog pain scale and by verbal rating scores of pain relief at 8-h intervals for up to 72 h after surgery. The cumulative dose of morphine at 72 h was smaller in the Propacetamol group than in the Placebo group (60.3 +/- 20.5 vs 112.2 +/- 39.1 mg; P < 0.001). The pain scores were significantly lower in the Propacetamol group measured at two intervals of the study, although visual analog scale pain intensity scores were smaller than 3 in both groups. Most patients in the Placebo group obtained a greater degree of sedation on postoperative Day 3 (P < 0.05). This study demonstrates the usefulness of propacetamol as an adjunct to PCA morphine in the treatment of postoperative pain after spinal fusion.

The “Tocopherol−Acetaminophen Reaction” − A New [1,4]-Rearrangement Discovered in Vitamin E Chemistry

Treatment of N-{4-[3,4-dihydro-6-hydroxy-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-5-ylmethoxy]phenyl}acetamide (8a) − the Toc prodrug of acetaminophen (7) − with aqueous base yields 4-hydroxy-3-(6-O-α-tocopheryl)acetanilide (10a) as the main product. This hitherto unknown reaction type can formally be regarded either as a rearrangement involving [1,4]-sigmatropic and [1,3]-sigmatropic shifts, or as an intramolecular redox process. Alternative pathways, such as an intermolecular reaction or a free radical process, have been ruled out. The formation of 10a by a multi-step sequence consisting of elimination, redox reaction, 1,4-addition to a quinone intermediate, and rearomatization has also been ruled out, by trapping reactions. During the reaction, a proton from the acetaminophen structure is selectively transferred to C-5a in the tocopheryl moiety as proven by deuteration experiments. The 4′-N-acyl structure is crucial for the reaction to proceed, with the N-acetyl group giving the highest yield of rearrangement product. As 5a-substituted tocopherols are also intermediates in many homolytic reactions of tocopherols in biological model systems, this type of rearrangement might well contribute to the “prooxidative effect” of α-tocopherol, with acetaminophen being replaced by other 5a-substituents that exhibit similar chemical behavior in the reaction.

Propacetamol: from basic action to clinical utilization

To review pharmacology and therapeutic use of propacetamol, an injectable prodrug of acetaminophen (paracetamol). Extraction from the Medline database of French and English articles on pharmacology and clinical use of propacetamol. Articles providing new data into the mechanisms of the analgesic action of paracetamol. Selection of controlled studies (original articles and abstracts of oral communications on therapeutic trials with propacetamol as a single agent or part of balanced analgesia protocols). Case reports and letters to the editor were not considered in this analysis. Clinical articles were selected for advantages and adverse effects of propacetamol. Articles dealing with mechanisms of action of propacetamol and paracetamol were selected for the more recent data, excluding those reporting outdated theories not confirmed or abandoned. Mechanisms of action of paracetamol differ from those of NSAIDs, giving account of a low risk of adverse renal, gastrointestinal and haematological effects. Thanks to their high therapeutic index, prescription of propacetamol and paracetamol is quite simple and safe. Main indications of both drugs are painful conditions, especially but not exclusively in the postoperative period, not requiring opioids and also in combination with other analgesic drug and/or techniques (balanced or multimodal analgesia). Because of cost, IV propacetamol is changed for oral paracetamol as soon as possible.

Structure of a monoclinic polymorph of N-[4-(acetyloxy)-phenyl]acetamide, a prodrug of acetaminophen

The preparation, single crystal x-ray structure and the computed powder XRD pattern of a monoclinic polymorph of N-[4-(acetyloxy)phenyl]acetamide, a prodrug of acetaminophen, are reported. The polymorph crystallizes in the space group P21/n with Z = 4 and unit cell dimensions a = 7.219(2), b = 8.015(2), c = 16.575(2) A, β = 92.07(1)°, and V = 958.4(4) A3. Infinite spiral molecular arrays result from intermolecular head-to-tail hydrogen bonding between the amidic H atom of one molecule and the acetoxy carbonyl oxygen atom of a 21-related molecule.

INTRAVENOUS TRAMADOL COMPARED TO PROPACETAMOL FOR POSTOPERATIVE ANALGESIA FOLLOWING THYROIDECTOMY

S267 INTRODUCTION: The aim of this randomized double-blind study is to compare the efficacy and side effects of Propacetamol, an injectable prodrug of Acetaminophen, 2g (P) and Tramadol, a weak synthetic opioid [1], 1.5 mg.kg-1 (T), given intravenously following thyroidectomy. METHODS: Following institutional approval, 80 patients undergoing thyroidectomy were divided into 2 groups (P or T). Propofol was used for induction (1-2 mg.kg-1) and maintenance (6 mg.kg-1.h-1) of anesthesia. Sufentanil boluses were injected when required. P or T was given once on request in the PACU (= t0). Residual pain was treated with Morphine using a IV PCA device. Pain and patients satisfaction were assessed using Visual Analog Scales (0-10). Sedation, occurrence of nausea and vomiting were recorded 2, 4 and 6 h after injection of the trial drug using four point rating scales. RESULTS: Demographic data and intraoperative Sufentanil use were comparable in group P and T. The same quality of analgesia was achieved in both groups as reflected by the cumulated morphine requirements, the VAS pain and VAS satisfaction scores. Every patient in each group required additional morphine. Sedation scores and incidence of nausea or vomiting (40 vs 46%; ns) were comparable in group P and T. CONCLUSIONS: Our study failed to show any difference in efficacy and side effects provided by a single intravenous dose of Propacetamol 2g or Tramadol 1.5 mg.kg-1. (Table 1 and Table 2)Table 1: Cumulated Morphine requirements (mg)Table 2: Visual Analog Scales

Cyclization-activated prodrugs: N-(substituted 2-hydroxyphenyl and 2-hydroxypropyl)carbamates based on ring-opened derivatives of active benzoxazolones and oxazolidinones as mutual prodrugs of acetaminophen.

N-(Substituted 2-hydroxyphenyl)- and N-(substituted 2-hydroxypropyl)carbamates based on masked active benzoxazolones (model A) and oxazolidinones (model B), respectively, were synthesized and evaluated as potential drug delivery systems. A series of alkyl and aryl N-(5-chloro-2-hydroxyphenyl)carbamates 1 related to model A was prepared. These are open drugs of the skeletal muscle relaxant chlorzoxazone. The corresponding 4-acetamidophenyl ester named chlorzacetamol is a mutual prodrug of chlorzoxazone and acetaminophen. Chlorzacetamol and two other mutual prodrugs of active benzoxazolones and acetaminophen were obtained in a two-step process via condensation of 4-acetamidophenyl 1,2,2,2-tetrachloroethyl carbonate with the appropriate anilines. Based on model B, two mutual prodrugs of acetaminophen and active oxazolidinones (metaxalone and mephenoxalone) were similarly obtained using the appropriate amines. All the carbamate prodrugs prepared were found to release the parent drugs in aqueous (pH 6-11) and plasma (pH 7.4) media. The detailed mechanistic study of prodrugs 1 carried out in aqueous medium at 37 degrees C shows a change in the Brönsted-type relationship log t1/2 vs pKa of the leaving groups ROH: log t1/2 = 0.46pKa-3.55 for aryl and trihalogenoethyl esters and log t1/2 = 1.46pKa-16.03 for alkyl esters. This change is consistent with a cyclization mechanism involving a change in the rate-limiting step from formation of a cyclic tetrahedral intermediate (step k1) to departure of the leaving group ROH (step k2) when the leaving group ability decreases. This mechanism occurs for all the prodrugs related to model A. Regeneration of the parent drugs from mutual prodrugs related to model B takes place by means of a rate-limiting elimination-addition reaction (E1cB mechanism). This affords acetaminophen and the corresponding 2-hydroxypropyl isocyanate intermediates which cyclize at any pH to the corresponding oxazolidinone drugs. As opposed to model A, the rates of hydrolysis of mutual prodrugs of model B clearly exhibit a catalytic role of the plasma. It is concluded from the plasma studies that the carbamate substrates can be enzymatically transformed into potent electrophiles, i.e., isocyanates. In the case of the present study, the prodrugs are 2-hydroxycarbamates for which the propinquity of the hydroxyl residue and the isocyanate group enforces a cyclization reaction. This mechanistic particularity precludes their potential toxicity in terms of potent electrophiles capable of modifying critical macromolecules.

The morphine-sparing effect of propacetamol in orthopedic postoperative pain

The analgesic efficacy and safety of propacetamol (Pro-Dafalgan), an injectable prodrug of acetaminophen, in combination with morphine administered by patient-controlled analgesia (PCA) were studied in 60 patients (56 men, 4 women; age 18–40 years; mean age, 26 years) after knee ligamentoplasty. Using a double-blind, randomized, parallel-group design, the effects of four (every 6 hr) intravenous injections of 2 g propacetamol (= 1 g acetaminophen) were compared with four injections of placebo (PL) in the recovery room immediately after surgery. Efficacy was assessed over 24 hr by automatic recording on the PCA device of the cumulative dose of morphine and the number of boluses requested. It was also assessed on pain scores rated on a five-point verbal scale and a visual analogue scale before administration, at 1, 2, 3, and 4 hr, and then every 2 hr until the 24th hr after administration. A five-point global efficacy scale was also administered. Any side effects were recorded throughout the duration of the study, and the ability to tolerate the drug was assessed by recording arterial pressure, cardiac and respiratory frequency, and sedation at the same assessment times as the pain scores. The 24-hr morphine consumption was significantly decreased in the propacetamol group (number of 1 mg boluses: 14.7 ± 11.3 versus 23.2 ± 13.8, P = 0.01; PCA usage: 26.4 ± 12.3 mg versus 34.6 ± 15.4 mg, P = 0.03; PCA usage + titration: 34.5 ± 12.7 mg versus 43.1 ± 15.9 mg, P = 0.02). Analysis of the hourly morphine doses showed a significant decrease from the fourth hr. There was no difference in pain scores between the two groups. Although there was also no significant difference in the global efficacy score, 75 % of patients in the propacetamol group versus 58% ( P = 0.21) found it “good” or “very good.” No difference was observed in safety criteria and four side effects were recorded: one in the propacetamol group and three in the placebo group. In conclusion, propacetamol has demonstrated a morphinesparing effect (⋍ 37%) in orthopedic postoperative pain, thus confirming that it is a useful and safe injectable non-NSAID, nonopioid analgesic in postoperative period.

Synthesis and evaluation in vitro of 4-acetamidophenyl phosphate.

4-Acetamidophenyl phosphate was synthesized by a phosphorylation procedure with polyphosphoric acid to examine its properties as a prodrug of acetaminophen. Separation of the ester from the phosphorylation mixture was carried out by precipitation with organic solvents. 4-Acetamidophenyl phosphate was soluble in water, was practically tasteless, and was quickly hydrolyzed to acetaminophen by alkaline phosphatase at 37°. The ester was stable in aqueous solution at neutral and acidic pH at 37°.

ChemInform Abstract: ACETAMINOPHEN PRODRUG, 2‐(P‐ACETAMINOPHENOXY)TETRAHYDROPYRAN

Abstractp‐Acetaminophenol (I) wird mit Dihydropyran (II) in Methylenchlorid in Gegenwart von Chlorwasserstoff zu dem Tetrahydropyranderivat (III) umgesetzt.

4-Acetamidophenyl 2,2,2-Trichloroethyl Carbonate: Particle Size Studies in Animals and Man

4-Acetamidophenyl 2,2,2-trichloroethyl carbonate (ATC) was prepared in coarse, regular, and fine particle sizes by sieving and grinding. The powders were found to dissolve in water at significantly different rates in a mechanically stirred system. When administered orally in suspensions to mice, the LD 50 's of the ATC powders were as follows: coarse—3340 mg./Kg.; regular—2461 mg./Kg.; and fine-1796 mg./Kg. The three ATC powders produced significantly different blood plasma concentrations of total acetaminophen in mice during the 0- to 2-hr. period after oral administration. In humans, the blood plasma concentration curves produced by oral administration of coarse and regular ATC were nearly identical. However, both had lower peaks and slower rates of decline than those produced by fine particle ATC or acetaminophen. Forty-eight-hour recovery of acetaminophen from human urine indicated that all the ATC powders were as efficiently absorbed as acetaminophen itself. It was concluded that ATC is a true prodrug of acetaminophen and that the acetaminophen blood plasma concentrations produced by orally administered ATC can be controlled to some degree by controlling its particle size.