Japrolox Mechanism of Action

Pharmacology: JAPROLOX TABLETS has excellent analgesic and anti-inflammatory effect, and its analgesic effect is specifically powerful. This drug has pharmacological characteristics such as a relatively lower toxicity to the gastrointestinal tract than other non-steroidal analgesic and anti-inflammatory drugs because it is the prodrug showing the effect after absorption from the gastrointestinal tract and conversion to active metabolites.
The mode of action of this drug is prostaglandin biosynthesis inhibition and its site of action is cyclooxygenase.
After oral administration, JAPROLOX TABLETS is rapidly absorbed from the digestive tract in the unchanged form causing weak irritation to the stomach mucosa, and then rapidly converted to an active metabolite, the trans-alcohol form (in SRS configuration) which potently inhibit prostaglandin biosynthesis.
Urinary excretion of JAPROLOX TABLETS is rapid and most amount of the drug administered is excreted in the unchanged form or in the glucoronic acid conjugated trans-OH form.
About 50% of the dose are excreted in the urine within 8 hours after administration.
Pharmacokinetics: Absorption and Metabolism: In sixteen healthy adult volunteers, JAPROLOX TABLETS was absorbed rapidly following a single 60-mg oral dose, and loxoprofen (unchanged drug) and its trans-OH form (active metabolite) were demonstrated in blood. The time to peak plasma concentration was about 30 minutes for loxoprofen and about 50 minutes for the trans-OH form, with an approximate half-life of 1 hour and 15 minutes for both compounds. (See Figure 1.)

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Drug-Metabolizing Enzymes: Loxoprofen sodium hydrate did not affect the metabolism of the various drugs that serve as the substrates for cytochrome P450 isoforms (CYP1A1/2, 2A6, 2B6, 2C8/9, 2C19, 2D6, 2E1, and 3A4), even at concentrations approximately 10 times as high as its peak plasma concentration (200 μM) in a metabolic inhibition study with human liver microsomes in vitro.
Pharmacokinetics Parameters (single dose): Absorption rate constant and elimination rate constant: See Table 1.

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Plasma protein binding rate: The plasma protein binding rate, as determined in humans (5 subjects at 1 hour after dosing of 60-mg JAPROLOX TABLETS) was 97.0% and 92.8% for loxoprofen and the trans-OH compound, respectively.
AUC (n=16, Mean±S.E.): Loxoprofen: 6.70±0.26 μg·hr/mL.
Trans-OH form: 2.02±0.05 μg·hr/mL.
Excretion: JAPROLOX TABLETS is rapidly excreted in urine; it is excreted largely as glucuronate conjugates of loxoprofen and the trans-OH compound. (See Figures 2, 3 and Table 2.)

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Absorption and Excretion Following Multiple Doses: Absorption and excretion of JAPROLOX TABLETS after oral administration at 80 mg t.i.d. for 5 days in five healthy adult volunteers did not noticeably differ from those after a single oral dose; hence no evidence of accumulation.