Pharmacokinetics of Zelmac

Rapid absorption (Tmax= 1 hour)

Dose-proportional pharmacokinetics in the range2–12 mg b.i.d.

Metabolism

– inactive metabolites

– approximately 60% excreted unchanged in feces

T½= 10.8±4.6 hours

No effect of age or gender on pharmacokinetic profile

Appel-Dingemanse 2002

Rapid Absorption

With 1 hour Zelmac reaches peak plasma

concentration

Absorption- in relation to food intake

• Absolute bioavailability in fasted subjects is approximately 10%.

•The presence of food increases the time to reach Cmax

to approximately 2 hours. The rate and extent of absorption are reduced after medium and high fat meals

•Any decrease in plasma concentration after a meal is thought to result from changes in absorption

What does this mean in terms of time of dose ?

This supports the recommendation that Zelmac be taken before a meal

Distribution

In the circulation, approximately 98% of Zelmac is bound to plasma protein, principally to alpha 1-acid glycoprotein.

Saturation would only occur at concentrations well above therapeutic levels.

Zelmac and the Blood Brain Barrier

The blood-brain permeability of Zelmac is low mainly due to its high polarity and molecular weight, giving limited potential for CNS side effects.

Metabolism

The metabolism of Zelmac has been studied extensively.

Zelmac is metabolized by two routes: either hydrolysis in the stomach or systemically by direct N-glucuronidation.

Elimination

58% is eliminated unchanged in the feces

27% is the inactive metabolite in the urine. 5-methoxy-indol-3-carboxylic acid glucuronide

No unchanged Zelmac is recovered in urine.

What does this mean???

It means…

Zelmac is eliminated mainly through the liver

Patients with mild to moderate hepatic problems can take Zelmac without dose adjustment–

We do not recommend it for patients with severe hepatic impairment

It means…

Zelmac is filtered and excreted in the Kidney

Patients with mild to moderate renal problems can take Zelmac without dose adjustment–

We do not recommend it for patients with severe renal impairment