Clinical Pharmacokinetics of Hypolipidaemic Drugs

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Abstract

Summary

Since hypolipidaemic drugs are widely used, despite the still unanswered question whether lowering of plasma lipids has a protective effect on the development of atherosclerosis, discussion of the clinical pharmacokinetics of the main representatives of this group of drugs is warranted.

Clofibrate is quantitatively transformed to its active metabolite, chlorophenoxyisobutyric acid (CPIB), immediately after oral administration. Absorption of CPIB is complete, but relatively slow with peak concentrations being attained 2 to 6 hours after the dose. The apparent volume of distribution is between 6 and 12 litres; plasma protein binding is higher than 90%, but is reduced in the nephrotic syndrome, in renal failure, and in cirrhosis. The elimination half-life of CPIB ranges between 10 and 25 hours, is shorter in patients with the nephrotic syndrome, but is prolonged in renal failure in close correlation with the degree of renal impairment. The plasma clearance of the total drug (mean of 7ml/min) appears to be increased in the nephrotic syndrome, but is decreased in renal failure and is unchanged in liver cirrhosis. Clearance of the unbound drug (mean of 240ml/min) is markedly reduced in renal failure, but is also reduced in liver cirrhosis. No pharmacokinetic changes are observed in acute hepatitis. Urinary excretion of CPIB is normally 10 to 15% of the dose; excretion is reduced in renal failure, but is unaffected in the nephrotic syndrome and in liver cirrhosis.

Nicotinic acid is rapidly absorbed with peak concentrations being attained after 45 minutes. The systemic availability is about 90%. Accumulation of the drug is reported in red blood cells, but no information is available on its distribution and on its plasma protein binding. The plasma elimination half-life is about 45 minutes. One third of an oral dose is excreted in urine unchanged. With pharmacological doses the major metabolite is nicotinuric acid; other metabolites being N-methyl-nicotinamide, 2-pyridone, and 4-pyridone, respectively. A measurable pharmacological effect is achieved with plasma concentrations of 0.1 to 0.2μg/ml, while a therapeutic range of 0.5 to 1.0μg/ml is suggested. Flushing of the skin is reported to-occur only at the beginning of treatment when the plasma concentration of nicotinic acid increases. Several analogues of nicotinic acid have been developed with the intention of achieving a sustained effect by a gradual in vivo liberation of nicotinic acid.

Cholestyramine is not absorbed from the gastrointestinal tract. As it is an anion exchange resin it may interfere with the absorption of a number of drugs by binding them to the resin.

β-Sitosterol absorption is normally less than 5%, but has been 25% in 2 sisters, so that a genetically determined influence on absorption is assumed.

Dextrothyroxine possesses only a small fraction of the hypermetabolic activity of its levoisomer. Absorption is between 40 and 50%, but is decreased in malabsorption syndromes and in some patients with liver cirrhosis. Plasma protein binding is higher than 99%. The elimination half-life is 6 to 7 days, but is decreased in hyperthyroidism and increased in hypothyroidism. Thyroxine is completely metabolised after oral dosing, one metabolite with pharmacological activity being triiodothyronine.

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