Diclofenac pharmacokinetics

No clinically important pharmacokinetic interactions have been found to occur between aspirin 975 mg and misoprostol 200 micrograms, or between ibuprofen and misoprostol. One study found that misoprostol 800 micrograms daily decreased the AUC of a single 100-mg dose of diclofenac by a modest 20%. However, other studies have found that misoprostol had no effect on steady-state diclofenac pharmacokinetics. One study found that misoprostol 200 micrograms raised the steady-state levels of indometacin 50 mg three times daily by about 30%, whereas another found that misoprostol 400 micrograms twice daily reduced the AUC of indometacin 50 mg twice daily by 13% after one dose and reduced the maximum steady-state plasma concentration by 24%. These modest changes in serum indometacin levels are unlikely to be clinically important. 

Pharmacokinetics The pharmacokinetics following oral administration of a single dose or multiple doses of diclofenac/misoprostol to healthy subjects under fasted conditions are similar to the pharmacokinetics of the 2 individual components. Food decreases the multiple-dose bioavailability profile of both formulations. 

GFJ has been shown to increase the exposure of carbamazepine (175), cisapride (176-179), fluvoxamine (184), losartan (188), methadone (189), scopolamine (191), and sertraline (192). However, only the interaction of GFJ with carbamazepine and cisapride seems to be clinically relevant. No alteration in exposure was observed for clozapine (180,181), heophylline (195), halo-peridol (196), and omeprazole (190). Reports of increased pharmacokinetic parameters of clozapine, theophylline, and haloperidol suggest that an interaction is unlikely to be clinically relevant. Contradicting results were reported for itraconazole (185-187), digoxin (75,183), and sildenafil (193,194). An increased effect on concomitant use of diclofenac and GFJ was observed in rats (182). Overall, the clinical relevance for this drug class appears to be low. 

Damkier P, Hansen LL, Brosen K. Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine. Br J Clin Pharmacol 1999 48(6) 829-838. 

Diclofenac is a phenylacetic acid derivative that is relatively nonselective as a COX inhibitor. Pharmacokinetic and dosage characteristics are set forth in Table 36-1. 

The pharmacokinetics of diclofenac have been investigated in calves and swine. In the former species, plasma levels were 5.4 ppm at 15 min postdosing... 

Todd, P. A. and Sorkin, E. M. Diclofenac sodium. A reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, Drugs 1988, 35, 244-285. 

This chapter concentrates on some drug choices in acute rather than chronic pain, but the same principles can be used to determine the appropriateness of other types of analgesic. The drugs considered in this section are paracetamol, non-steroidal anti-inflammatories (NSAIDs specifically diclofenac, ibuprofen, indometacin, naproxen, sulindac and tenoxicam) and opioids (codeine, dihydrocodeine, morphine, pethidine and tramadol). Unless otherwise stated, all pharmacokinetic data originate from standard reference sources [1-5] and apply to adults only. 

Lill JS, O Sullivan T, Bauer LA, et al. (2000) Pharmacokinetics of diclofenac sodium in chronic active hepatitis and alcoholic cirrhosis. J Clin Pharmacol 40 250-257. 

The risk of ciclosporin-induced nephrotoxicity can be increased when NSAIDs are also used (44,45). Diclofenac in particular should be avoided, because it is more likely to cause deterioration of renal function in patients taking ciclosporin (SEDA-15, 100) (SEDA-17, 107). There is also a pharmacokinetic interaction, which may be caused by inhibition by ciclosporin of the first-pass metabolism of diclofenac (SEDA-21,104). 

In 16 healthy volunteers there were no important pharmacokinetic changes when a single dose of ciclosporin was taken during steady-state administration of aspirin, indometacin, or piroxicam, but there was an interaction with diclofenac, whose AUC was doubled in the presence of ciclosporin (46). 

In 30 healthy young men the pharmacokinetics of a single oral dose of quinidine 200 mg were studied before and during the daily administration of diclofenac 100 mg (a substrate of CYP2C9) (63). The clearance of quinidine by A-oxidation was reduced by diclofenac, but only by 27%. This small effect of diclofenac suggests a minor role for CYP2C9 in the metabolism of quinidine. 

Example Diclofenac sodium (Voltaren) and Ketorolac (Toradol) Route PO/ IM/IV Ophthalmic Pregnancy category B Pharmacokinetic Absorbed from the GI tract, metabolized in the liver, and primarily excreted in urine PB 99% not removed by hemodialysis... 

N. M. Idkaidek, G. L. Amidon, D. E. Smith, N. M. Najib, and M. M. Hassan, Determination of the population pharmacokinetic parameters of sustained-release and enteric-coated oral formulations, and the suppository formulation of diclofenac sodium by simultaneous data fitting nsing NONMEM. Biopharm Drug Dispos 19 169-174 (1998). 

I. Mahmood, Pharmacokinetic analysis of the absorption characteristics of diclofenac sodium in man by use of a multi-segment absorption model. J Pharm Pharmacol 48 1260-... 

Brenner SS, Herrlinger C, Dilger K, et al. Influence of age and cytochrome P450 2C9 genotype on the steady-state disposition of diclofenac and celecoxib. CUn Pharmacokinet 2003 42 283-292. 

Sintov et al. evaluated the pharmacokinetics of diclofenac from three formulations, viz. topical emulgel (Voltaren emulgel), topical microemulsion and subcutaneous injection... 

Figure 9.2 Pharmacokinetic profiles of diclofenac in rats after transdermal administration of Voltaren Emulgel and microemulsion compared to subcutaneous administration. The microemulsion formulation was superior to Voltaren Emulgel with respect to transdermal delivery and acted for longer time as compared to subcutaneous injection. (Figure redrawn with data from Ref. [59], reprinted with permission of Elsevier.)...

Ramakrishna, S. Fadnavis, N.W. Diwan, P.V. Comparative pharmacokinetic evaluation of compressed suppositories of diclofenac sodium in humans. Arzneimittelforschung, 1996, 46, 175-177... 

Avgerinos, A. Karideis, T. Malamataris, S. Extractionless high-performance Uquid chromatographic method for the determination of diclofenac in human plasma and urine. J.Chromatogr., 1993, 619, 324-329 [plasma urine indomethacin (IS) column temp 40 LOD 200 ng/mL pharmacokinetics]... 

De Bernard di Valserra, M. Feletti, F. Tripodi, A.S. Contos, S. Carabelli, A. Maggi, L. Germogli, R. Pharmacokinetic studies in heedthy volunteers on a new gastroprotective pharmaceutic form of diclofenac. Arzneimittelforschung, 1993, 43, 373-377 [plasma coliunn temp 30 LOD 20 ng/mL pharmacokinetics]... 

Sioufi, A. Richard, J. Mangoni, R Godbillon, J. Determination of diclofenac in plasma using a fully automated analytical system combining liquid-solid extraction with liquid chromatography. J.Chromatogr., 1991, 565, 401-407 [plasma SPE pharmacokinetics LOQ 31 nM]... 

Plavsic, F. Culig, J. Determination of serum diclofenac by high-performance liquid chromatography by electromechanical detection. Hum.ToxicoL, 1985, 4, 317-322 Said, S.A. Sharaf, A.A. Pharmacokinetics of diclofenac sodium using a developed HPLC method. Arz-neimittelforschung, 1981, 31, 2089-2092... 

Macek, J. Vacha, J. Rapid and sensitive method for determination of piroxicam in human plasma by high-performance liquid chromatography. J.Chromatogr., 1987,420, 445-449 [column temp 35 glass column LOD 150 ng/mL pharmacokinetics simultaneous antipyrine, diclofenac, hydroxychloroquine, ibuprofen, isoxicam, plaquenil, sulfamethazine]... 

Celecoxib is currently indicated for the relief of signs and symptoms of osteoarthritis and rheumatoid arthritis and to reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis as an adjunct to usual care. Celecoxib is at least as effective as naproxen in the symptomatic management of osteoarthritis and at least as effective as naproxen and diclofenac in the symptomatic treatment of rheumatoid arthritis, and it is less likely to cause adverse Gl effects. Celecoxib appears to be effective in the management of pain associated with both of these arthritic conditions, but effectiveness in acute or chronic pain has not been fully demonstrated. Unlike aspirin, celecoxib does not exhibit antiplatelet activity. Concomitant administration of aspirin and celecoxib may increase the incidence of Gl side effects. Another notable potential drug interaction with celecoxib is its ability, like other NSAIDs, to reduce the blood pressure response to angiotensin-converting enzyme inhibitors. A more detailed discussion of the chemical, pharmacological, pharmacokinetic, and clinical aspects of celecoxib is available (81). 

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