Metabolism of Meloxicam in human liver involves cytochromes P4502C9 and 3A4

Abstract

1. The metabolism of Meloxicam (ME) and the cytochrome(s) P450 (CYPs) involved were analysed by using primary human hepatocytes, human liver microsomes and microsomes from recombinant human B-lymphoblastoid cell lines. 2. While human hepatocytes were capable of converting ME to a 5-hydroxymethyl metabolite (M7) and then to a 5-carboxyderivative (M5), human liver microsomes formed mostly only the 5-hydroxymethylderivative. The kinetics of the formation of M7 by human liver microsomes were biphasic with Km = 13.6 +/- 9.5 and 381 +/- 55.2 microM respectively. The corresponding Vmax were 33.7 +/- 24.2 and 143 +/- 83.9 pmol/min/mg protein respectively. 3. CYP2C9 and, to a much lesser extent, CYP3A4 were found to convert ME to M7. The involvement of 2C9 was demonstrated by inhibition of tolbutamide hydroxylase activity in the presence of ME, inhibition of ME metabolism by sulphaphenazole, correlation between ME metabolism and tolbutamide hydroxylase activity and active metabolism of ME by recombinant 2C9. The involvement of 3A4 was shown by inhibition of ME metabolism by ketoconazole, correlation between ME metabolism and nifedipine oxidase activity and metabolism of ME by recombinant 3A4. Kinetics of the formation of M7 by the individual enzymes resulted in a Km = 9.6 microM and Vmax = 8.4 pmol/min/mg protein for 2C9 and a Km = 475 microM and Vmax = 23 pmol/min/mg protein for 3A4.

Population pharmacokinetic analysis of meloxicam in rheumatoid arthritis patients

“…Meloxicam is mainly metabolized by CYP2C9 [3]. The increase in meloxicam clearance observed in the present study after coadministration of sulphasalazine suggests that induction of CYP2C9 has occurred.…”

“…Peak plasma concentrations are reached 5-6 h after oral dosing when taken concomitantly with a light meal, as generally recommended [2]. Meloxicam undergoes extensive metabolism, primarily by cytochrome P450 CYP2C9 and to a minor extent by CYP3A4 [3], forming four major inactive metabolites [1,4]. The pharmacokinetics of meloxicam are linear over the dose range 7.5-30 mg and remain unchanged from single to multiple dosing [5].…”

Effect of Andrographolide Co-Administration on Pharmacokinetics of Meloxicam in Rats

“…However, no significant effect of andrographolide on pharmacokinetics of warfarin (Hovhannisyan et al, 2006) and midazolam (Wongnawa et al, 2012) was observed. Alteration in pharmacokinetic of meloxicam may be due to metabolism of meloxicam caused by major extent through CYP2C9 and, to a much lesser extent, CYP3A4 (Schmid et al, 1995;Chesné et al, 1998) and andrographolide was also found to modulate expression of CYP2C9 and CYP3A4 microsomal enzyme (Pekthong et al, 2008;Pekthong et al, 2009).…”

“…Meloxicam has a high intrinsic activity combined with a low ulcerogenic potential (i.e. a high therapeutic index) (Engelhardt et al, 1996).Meloxicam is considered as standard non-steroidal antiinflammatory drug which metabolized by the cytochrome P450 (CYP) subgroup of isoenzymes, possibly CYP2C9/2C8 and CYP3A4 (Schmid et al, 1995;Chesné et al, 1998). Andrographolide (diterpene lactone) is main chemical constituent of plant Andrographis paniculata.…”

“…Moreover, it is reported that andrographolide modulate expression of several cytochromes P450 isoenzymes like CYP2C9, CYP3A4, CYP2C6/11, CYP1A1/2 and CYP3A1/2. (Chesné et al, 1998;Schmidet al, 1995;Pekthong et al, 2008; The pharmacokinetic of meloxicam (5 mg/kg) and effect of co-administration of andrographolide (50 mg/kg) on pharmacokinetics of meloxicam were studied following intramuscular administration in rats. Drug concentration in plasma was determined using High Performance Liquid Chromatography (HPLC).…”