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Cure Arthritis Naturally

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Symbols and abbreviations: Cmax = maximum plasma concentration; tmax = time to Cmax; C12 drug concentration observed in plasma 12 h after administration; AUC0_12 and AUC = area under the plasma concentration-time curve from 0 to 12 h and to infinity; ty2z = apparent terminal half-life; Rmax = ratio of Cmax at steady state to Cmax after the first dose; Rmin = ratio of trough concentrations (C12) at steady state and after the first dose; Rav = ratio ofAUC0_12 values at steady state and after the first dose; M = males; F = females; bid = twice daily after a standard American breakfast resulted in Cmax of approximately 20% lower than that obtained under fasting conditions [23]. However, neither tmax nor AUC were significantly modified by food intake (Tab. 6). For the main nimesulide metabolite, M1, the Cmax, tmax, and AUC values after a meal were similar to those under fasting conditions (Tab. 8).

Distribution

The plasma concentration-time profiles obtained after oral administration of nimesulide have mostly been analysed in accordance with a model-independent approach. In some studies, a bi-exponential modelling was proposed, in which the first exponential term represented the absorption process and the second the elimination process [28, 30]. A clear-cut distribution phase cannot be usually identified from the plasma concentration-time curve by use of a semi-logarithmic scale, indicating that the nimesulide distribution process is fast. Therefore, a one-compartment open model is generally appropriate to describe the pharmacoki-netic profile of nimesulide after oral administration. In a few individuals the plasma kinetic profile was described by a tri-exponential equation [30]. In such cases, a definite distribution phase emerged, and a two-compartment open model was considered to be more appropriate for describing the data.

The extent of drug distribution can be evaluated by estimation of the volume of distribution in the post-distribution phase (Vz/F), which represents the actual volume of distribution, assuming that F is close to unity (see 'Absorption' section). After single oral 100 mg dose administration, Vz/F values range from 0.18-0.39 L/kg (Tab. 6), indicating that nimesulide is mainly distributed in the extracellular fluid compartment. Nearly all NSAIDs have a relatively small volume of distribution, Vz/F usually ranging from 0.1-0.2 L/kg [43-50]. In fact, with the exception of salicylates [46], NSAIDs are generally extensively bound to human serum albumin and less than 1% of the total plasma concentrations are in an unbound form, available to distribute to extravascular tissues [43]. On the basis of the low estimates of Vz/F, there is no evidence that nimesulide might accumulate in tissue compartments.

Specific distribution studies have been performed with oral nimesulide in female genital tissues [51] and in the synovial fluid of patients with rheumatoid arthritis [52]. Twelve women undergoing hysterectomy and salpingo-oophorec-tomy received a single oral dose of nimesulide 100 mg 1-6 h before surgery. The nimesulide concentrations in the cervix, fundus, oviduct and ovaries ranged from 0.3-0.55 mg/g at 1 h, 0.58-0.97 mg/g at 2 h, 1.11-1.79 mg/g at 4 h, and 0.370.76 mg/g at 6 h. Although cervical tissue comprises mainly collagen and fundal uterine tissue comprises smooth muscle, there was no significant difference in the distribution of nimesulide. At the fourth hour, when tissue concentrations were highest, the tissue-to-serum ratio was lower than the unity, as observed in the rat, ranging from 0.39-0.62 [51]. A good clinical response to nimesulide was seen patients with dysmenorrhoea and corresponded to the distribution of the drug in the genital tissues [32].

The penetration of nimesulide into the articular cavity was evaluated in six patients with rheumatoid arthritis treated with nimesulide 100 mg tablets twice daily for 7 days. Three and 12 h after the last dose, nimesulide concentrations in the synovial fluid were 2.39-1.38 mg/L, respectively. The synovial fluid-to-plasma concentration ratios were 0.44 (3 h) and 0.54 (12 h) [52].

Binding to blood components

The low tissue:plasma and synovial fluid:plasma ratios may be related to high plasma protein binding, as with other NSAIDs, which keeps the drug predominantly in the plasma compartment. The plasma protein binding of nimesulide has been studied in vitro using equilibrium dialysis. In a first study, at plasma concentration of 0.5-10 mg/L, the unbound fraction (fu) of nimesulide in human plasma varied from 0.7-4%, which is indicative of extensive plasma protein binding [53]. In a second study, the serum binding of nimesulide was constant (fu 1%) over the concentration range of 0.77-20 mg/L [54]. Using pure human serum albumin (735 mM), nimesulide binding was non-saturable and super-imposable to that observed using human serum. A weak binding to aracid glycoprotein and lipopro-teins was observed, whereas there was no binding to gamma-globulin. Erythrocyte-bound nimesulide was found only in the buffer rather than in plasma, indicating a strong affinity for plasma proteins [54].

After oral administration of 100 mg [14C] nimesulide to healthy volunteers, the whole blood:plasma ratio of mean total radioactivity was approximately 0.6 at 4, 8 and 24 h. This suggests that nimesulide (and minor other radiolabeled components) are not associated in vivo with blood cells and do not significantly enter the erythrocytes [36].

Elimination

After single dose oral administration of nimesulide 100 mg, plasma concentrations of the parent drug declined mono-exponentially following the peak. The apparent mean elimination half-life (t1/2,z) varied from 1.80-4.73 h (Tab. 6). The variation in t1/2,z values can, at least in part, be attributed to the different methods of data analysis used - non-compartmental analysis in some studies [19, 23-27], multi-exponential modelling (bi- or tri-exponential models) with the use of weighting factors, in others [28, 30].

The total plasma clearance (CL/F) of nimesulide varied from 31.02-106.16 mL/h/kg after oral administration of a 100 mg dose, and was almost exclusively attributable to metabolic clearance (Tab. 6). Nimesulide is a low-clearance drug: assuming that the liver is the only organ for metabolising this drug and that the absorption across the gut wall is complete (F = 1), the hepatic extraction ratio, calculated from the ratio of CL/F to hepatic plasma flow, is approximately 0.1. As a consequence of the low extraction ratio, the CL/F of nimesulide may, in principle, vary proportionally with any possible change in fu caused by physiopatho-logical factors or drug-drug interactions.

Excretion

The excretion of the parent drug in urine and faeces resulted to be negligible in most of oral [18, 33-39] and rectal [55] administration studies, with only 6.3-8.7% of the parent drug found in faeces after [14C] nimesulide administration [34, 36]. Indeed, nimesulide is mainly eliminated following metabolic transformation.

In dose balance studies involving oral administration of [14C] nimesulide [34, 36], 78.1-98.7% of the radiolabeled dose was recovered, of which urinary excretion accounted for 50.5-62.5% and faecal excretion 17.9-36.2% of the administered dose (Tab. 7). These results indicate that nimesulide and its metabolites are mainly excreted by the renal route.

Figure 4

Mass balance of [14C] nimesulide in healthy volunteers after oral administration of 100 mg radiolabeled drug. Percent of administered dose excreted in urine ( ■ ), faeces ( • ) and in total (± ).

Figure 4

Mass balance of [14C] nimesulide in healthy volunteers after oral administration of 100 mg radiolabeled drug. Percent of administered dose excreted in urine ( ■ ), faeces ( • ) and in total (± ).

In volunteers treated orally with unlabelled oral nimesulide 200 mg [37-39], urinary excretion of the known nimesulide metabolites accounted for 31.9-70.5% of the administered dose. Faecal excretion was 21.5% [37] (Tab. 7). The low urinary recovery of nimesulide in some studies with administration of unlabeled nimesulide is likely due to incomplete urine collection or incomplete mass balance (nimesulide metabolites identified later were not included in the mass balance estimation).

Metabolism

Nimesulide is extensively metabolised. A total of 16 metabolites of nimesulide were identified and the biotransformation of nimesulide in man was shown to proceed by three principle routes, cleavage of the molecule at the ether linkage, reduction of the NO2 group to NH2 and phenoxy ring hydroxylation. Other metabolites arise from the concomitant hydroxylation and reduction, acetylation of the amino group, conjugation with either glucuronic acid or sulphate of hydroxylated metabolites [34, 36, 56, 57].

A comprehensive determination of nimesulide metabolic pathway has been established in fasted male volunteers who received a single oral dose of 100 mg [14C] nimesulide [36]. Radiolabeled metabolites were identified by LC-MS and LC-MS/MS with reference to synthesised metabolite standards. Recovery of the dose was essentially quantitative (>97%) for all subjects. The major proportion of the administered radioactivity was excreted via urine, accounting for 59-66% (mean value 62.5%). Radioactivity excreted in the faeces accounted for a further 33-39% (mean value 36.2%). Greater than 92.4% of the urinary (0-24) radioactivity was now accounted for by characterised metabolites. Methanol extraction of faeces recovered approximately 60% of the faecal radioactivity and greater than 40% of this radioactivity was identified as nimesulide.

Nimesulide was identified in extract of faeces and in plasma. Cleavage of the ether linkage gives metabolite 6 which is conjugated with glucuronic acid to give metabolite 17. Reduction of the NO2 group to NH2 is proposed to produce the intermediate metabolite 2, which is hydroxylated to produce metabolite 3. Metabolite 3 is acetylated to produce metabolite 5. An alternative route is possible for the production of metabolite 5. It is proposed that metabolite 2 is acetylated to the postulated intermediate metabolite 4 which is in turn hydroxylated to give metabolite 5. This second pathway is less likely because the acetylation of the NH2 group is thought to occur in the kidney and therefore is a terminal metabolic reaction. Metabolite 5 is conjugated with sulphate and glucuronide to give metabolites 18 and 14, respectively. Ring hydroxylation of nimesulide gives metabolite 1; conjugation of this molecule with sulphate gives metabolite 9. Conjugation of metabolite 1 with glucuronic acid gives metabolite 10. It is proposed that the principle position of hydroxylation is consistent with the reference standard M1; however a

Figure 5

Metabolic pattern of nimesulide in humans (Based on data in Ref. 36)

Figure 5

Metabolic pattern of nimesulide in humans (Based on data in Ref. 36)

second position of hydroxylation is proposed to give rise to a second glucuronide conjugate of molecular weight 500 (metabolite 11). Metabolite 1 is hydroxylated in a second position to give metabolite 12 which is conjugated with glucuronide and sulphate to give metabolite 15 and 16, respectively. Greater than 92.4% of the urinary (0-24) radioactivity is accounted for by characterised metabolites.

MHsn HH MH.qn r.H

MHsn HH MH.qn r.H

nhcoch3 nhcoch3

nhcoch3 nhcoch3

Figure 6

Simplified metabolic patterns of nimesulide in humans (reproduced from A. Bernareggi [3] with permission).

The metabolites identified during this investigation extended the observations from previous studies [34, 37, 38, 56, 57] in which only 5 metabolites of nimesulide were found in human urine (M1-M5).

Metabolites M1, M2 and M5 were confirmed during the more recent study [36] but M3 and M4 were not detected. These metabolites were previously reported as being present at low concentrations. As a consequence they are proposed as intermediates in the full biotransformation pathway. Additional phase 1 metabolites (M6, M7 and M12) have been identified which were not previously detected. The structural assignments of M6 and M7 and their glucuronide conjugates were con firmed with authentic reference standards. A large portion of the administered dose of nimesulide was excreted as glucuronide and sulphate conjugates.

The main metabolites are represented by M1, found in plasma and urine, and M5, found in urine and faeces. In urine, M1 and M5 are present almost completely in conjugated form. In faeces, M5 is mainly unconjugated. Tables 7 and 9 provide comprehensive quantitative data of the excretion of unchanged nime-sulide and its metabolites according to the different authors.

No differences were observed in the metabolic profile between males and females [56].

The only important metabolite that can be followed in plasma is the 4'-hy-droxy-derivative, M1. Earlier studies indicated that the isozyme of the cytochrome P450 family CYP1A2, may be responsible for the hydroxylation of nimesulide to M1 [58]. However, it has also been proposed that CYP2C9 and CYP2C19 may be implicated in nimesulide hydroxylation reactions [59]. Other important enzymes involved in nimesulide biotransformation are the nitroreductases that are flavoproteins responsible for the reduction of nitro-arenes to amino-arenes through the formation of reactive species such as the nitroso-group and the hydroxyl-

Table 9 - Nimesulide metabolitite excretion in G-24 h urine [36]

Metabolite % administered dose

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