CLINICAL PHARMACOKINETICS OF NISOLDIPINE COAT-CORE

Nisoldipine, a calcium antagonist of the dihydropyridine type, is the active ingredient of the controlled release nisoldipine coat-core (CC) formulation. In humans, the absorption from nisoldipine CC occurs acr oss the entire gastrointestinal tract with an increase in bioavailabil ity in the colon because of the lower concentrations of metabolising e nzymes in the distal gut wall. Although nisoldipine is almost complete ly absorbed, its absolute bioavailability from the CC tablet is only 5 .5%, as a result of significant first-pass metabolism in the gut and l iver. Nisoldipine is a high-clearance drug with substantial interindiv idual and relatively lower intraindividual variability in pharmacokine tics, dependent on liver blood flow. Nisoldipine is highly (>99%) prot ein bound. Its elimination is almost exclusively via the metabolic rou te and renal excretion of metabolites dominates over excretion in the faeces. Although nisoldipine is administered as a racemic mixture, its plasma concentrations are almost entirely caused by the eutomer as a result of highly stereoselective intrinsic clearance. Nisoldipine CC d emonstrates linear pharmacokinetics in the therapeutic dose range and its steady-state pharmacokinetics are predictable from single dose dat a. Steady-state is reached with the second dose when the drug is given once daily and the peak-trough fluctuations in plasma concentration i s minimal. Plasma-concentrations of nisoldipine increase with age. Car eful dose titration according to individual clinical response is recom mended in the elderly. Nisoldipine CC should not be used in patients w ith liver cirrhosis, though dosage adjustments in patients with renal impairment are not necessary. Inter-ethnic differences in its pharmaco kinetics are not evident. Owing to inhibition of metabolising enzymes, a small dosage adjustment decrement for nisoldipine CC may be require d when it is given in combination with cimetidine. Concomitant ingesti on of nisoldipine with grapefruit juice should be avoided. Inducers of cytochrome P450 (CYP) 3A4, e.g, rifampicin (rifampin) and phenytoin s hould not be combined with nisoldipine 66, as they may reduce its bioa vailability and result in a loss of efficacy. The concomitant use of o ther drugs which may produce marked induction or inhibition of CYP3A4 is contraindicated. Concomitant intake of the CC tablet with high fat, high calorie foods resulted in an increase in the maximum plasma conc entrations of nisoldipine. This 'food-effect' can be avoided by admini stration of the CC tablet and the intake of food. Plasma concentration s of nisoldipine are related to its antihypertensive effect via a maxi mum effect model. Nisoldipine CC once daily produce reductions in bloo d pressure which are maintained over 24 hours in the absence of releva nt effects on heart rate.