Lercanidipine: Short Plasma Half-life, Long Duration of Action and High Cholesterol tolerance. Updated molecular model to rationalize its pharmacokinetic properties

Abstract

Calcium-channel antagonist drugs of the 1,4-dihydropyridine type have been shown to bind to the L-typecalcium channel. These drugs are not only amphiphilic, but new molecular designs have becomeincreasingly lipophilic and can readily transport across cell membranes, accessing both hydrophilic andhydrophobic environments, despite becoming more soluble in the membrane bilayer. This biophysicalunderstanding appears not only to define the molecular pathways for drug binding to the calcium-channelreceptor, but also to explain differences in the overall clinical pharmacokinetics observed for differentdrugs in this class. The pharmacokinetic profile of calcium antagonists, although influenced to somedegree by interactions with their target calcium-channel receptor, appears to be largely dictated by theirinteractions with cell membranes at the molecular level. There appears to be a correlation between theduration of action of such membrane-active drugs and the membrane partition coefficient in conjunctionwith the washout rate. This class of drugs has evolved from a drug such as amlodipine, with a longduration of action related to prolonged plasma half-life, to lercanidipine, which has the shortest plasmahalf-life relative to its intrinsically long duration of action. Recently, it was discovered that membranecholesterol reduces the amount of calcium-channel antagonist that can partition into the membrane.Atherosclerotic disease results in increased levels of membrane cholesterol in smooth muscle cells. Latestgeneration calcium antagonists, which have a long duration of action, can better overcome this negativeeffect. Lercanidipine has now been shown to have one of the highest measured tolerances to cholesterol,which may indicate its ability to treat a broad range of hypertensive patients with varying degrees ofprogressive atherosclerotic disease. On what criteria should the effectiveness of calcium antagonists beevaluated? A good calcium antangonist needs to exhibit a placebo-like side-effect profile, thus ensuringgood patient compliance. However, an intrinsically long-lasting, once-a-day dose is also pharmacokineticallydesirable. To be a truly optimal calcium antagonist, it should function and be efficacious over abroad range of hypertensive patients. It should be able to control blood pressure in light of othercomplications such as progressive atherosclerotic disease. Recent studies indicate that during theprogression of atherosclerosis, cholesterol levels within cell membranes of the arterial wall increase, aprocess that can reduce the effective concentration of calcium antagonists in these membranes. What isneeded is a calcium antagonist that is slow acting to reduce vasodilatory induced side-effects andintrinsically long lasting to ensure once-a-day dosage, and that possesses a high cholesterol tolerancefactor to overcome the molecular and compositional changes taking place in the arterial wall, so that itcan treat effectively a broad range of hypertensive patients.