Diclofenac glucuronide

Figure 6.43 H spectrum of diclofenac glucuronide obtained after single trapping from a 100 pi injection of female urine 4 h after dosage of 50 mg of diclofenac. The spectrum was recorded using a cryogenic flow probe at 600 MHz. The spectrum indicates that the sensitivity is sufficient to run aU two-dimensional experiments needed for structure elucidation. Reproduced from [82] with permission from Elsevier.

Diclofenac undergoes hepatic methylation and oxidation, creating (6 metabolites that are all susceptible to conjugation by glucuronidation and sulfation. A major metabolite of diclofenac is considered to be its hydroxylated derivative,... 

Figure 4.54 Interaction of the acyl glucuronide of diclofenac with protein. The small arrow indicates the reactive carbonyl carbon atom.

Acyl glucuronide Diclofenac Glucuronosyl transferase Hepatic toxicity... 

However, phase 2 conjugation can also on occasion produce electrophilic intermediates/ metabolites, such as the sulfate conjugation of hydroxytamoxifen (see chap. 7), and the formation of acyl glucuronides with acidic drugs such as diclofenac (Fig. 4.54). 

The plasma protein binding of diclofenac is greater than 99.5 % and the plasma elimination half-life is between 1 and 2 h. The metabolites of diclofenac, 4 -hydroxy-diclofenac, 5-hydroxydiclofenac, 3 -hydroxy-diclofenac, and 4 ,5-dihydroxydiclofenac are excreted as glucuronide and sulphate conjugates in the urine ( 65%) and in the bile (-35%). 

Kumar S, Samuel K, Subramanian R, et al. Extrapolation of diclofenac clearance from in vitro microsomal metabolism data role of acyl glucuronidation and sequential oxidative metabolism of the acyl glucuronide. J Pharmacol Exp Ther 2002 303 969-978. 

Diclofenac 50 >99 1-2 <1 Negligible, if at all Extensive in liver - CYP2C9-hydroxylation then sulphation/ glucuronidation. First-pass metabolism of 50% 4- and possibly 3-hydroxydiclofenac but negligible antiinflammatory activity compared to diclofenac... 

Ki etz-Rommel, A. Boelsterli, U.A. "Diclofenac Covalent Protein Binding is Dependent on Acyl Glucuronide Formation and is Inversely Related to P450-mediated Acute Cell Injury in Cultured Rat Hepatocytes," Toxicol. Appl. Pharmacol. 120(1), 155-161 (1993). 

Seitz, S. Boelsterli, U.A. Diclofenac Acyl Glucuronide, aMajor Biliary Metabolite, Is Directly Involved in Small Intestinal Injury in Rats, Gastroenterol. 115(6), 1476-1482 (1998). 

Diclofenac has rapid absorption, extensive protein binding, and a short t (Table 26-2). There is a substantial first-pass effect, such that only -50% of diclofenac is available systemically. Diclofenac accumulates in synovial fluid after oral administration, which may explain why its duration of therapeutic effect is considerably longer than the plasma t - Diclofenac is metabolized in the liver by a member of the CYP2C subfamily to 4-hydroxydiclofenac, the principal metabolite, and other hydroxylated forms after glucuronidation and sulfation the metabolites are excreted in the urine (65%) and bile (35%). 

Other important metabolites of O-glucuronidation are acylglucuronides. They are formed by esterification of carboxylic acids with glucuronic acid. Many therapeutic agents such as arylacetic acids (diclofenac, diflunisal), aliphatic acids (valproic acid) and arylpropionic acids (ketoprofen, naproxen) are metabolized as acylglucuronides (Fig. 31.37). 

Fig. 31.37 Substrates that form reactive glucuronides (1) ketoprofen (2) naproxen (3) clofibric acid (4) diclofenac (5) diflunisal (6) valproic acid (7) all-frans retinoic acid (8) bilirubin (9) A/-hydroxy-2-acetyTaminofluorene.

Some examples of bioactivation to hepatotoxic or IDR electrophilic intermediates are shown in Fig. 10.33. Bioactivation may occur by both oxidation and conjugation reactions, such as those with diclofenac, which undergoes the formation of an acyl glucuronide and/or acyl CoA (acylator intermediates) or to produce iminoquinones via formation of a phenol intermediator (Fig. 10.33-1) (92). The anticonvulsant carbamazepine is 2-hydroxylated and the elimination of the amide group yields the reactive quinoneimine intermediate (Fig. 10.33-2), and the antidepressant paroxetine and other xenobiotics with the common methylenedioxyphenyl nucleus undergo methylene oxidation to a... 

A single 50-mg dose of diclofenac sodium did not have an important effect on the pharmacokinetics of a single 100-mg dose of codeine phosphate in a placebo-controlled crossover study in 12 healthy subjects. There was no effect on the metabolic clearance of morphine, and only a slight (about 5% to 10%) increase in the levels of glucuronide metabolites. In addition, diclofenac did not alter the analgesic effects of codeine as assessed in a cold pressor test (a test in which opioids, but not NSAIDs, are effective). ... 

However, in eontrast to these reports, a study in 7 patients on the first postoperative day after spinal surgery found that, although diclofenac 100 mg rectally reduced patient-controlled morphine consumption by 20%, respiratory rates were significantly lower after the diclofenac, and minimal at about 200 minutes. Levels of an active metabolite, morphine-6-glucuronide did not significantly decrease until 420 minutes. ... 

Tighe KE, Webb AM, Hobbs GJ, Persistently hi plasma morphine-6-glucuronide levels despite decreased hourly patient-controlled andgesia morphine use after single-dose diclofenac potential for opioid-related toxicity. Anesth Amlg ( 999) 88,1137-42. 

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