The 1999 Glaxo Wellcome international achievement award was presented to Professor William Charman (Victorian college of pharmacy, Monash university, Melbourne, Australia) on September 14. In his award lecture, Professor Charman described advances in the understanding of factors influencing the formulation and bioavailability of lipophilic drugs
A renaissance in the use of lipid-based formulations over the past 10 years had resulted in the study of the effects of lipids on drug delivery becoming a hot area for research, said Professor Charman.
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William Charman: several benefits from lipid formulations |
There were many details to consider when using lipid formulations for drug delivery. In particular, it was important to appreciate the effects of both the drug and lipid components of the system on the drug handling processes within the gastrointestinal lumen, the enterocyte and the systemic circulation. From the point of view of the lipid component, it was necessary to consider matters of transit, digestion and solubilisation.
There were two pertinent features. First, the human body actually transported fats with high efficiency and absorbed about 95 per cent of a daily dose of dietary fats of 100g. Secondly, the increase in bile salt concentration from 3-6mM at rest to 10-20mM after food underpinned the considerable capacity for fat solubilisation via mixed-micelle formation. However, despite this apparently favourable environment for absorption of lipid-based systems, events "downstream" of solubilisation also had to be considered. For example, what was the effect of subsequent dissociation of the micelles at the apical membrane of the enterocytes?
With regard to the drug component (in a lipid formulation), it was often better to realise what the questions were rather than look immediately for answers, said Professor Charman. Did the drug remain associated with the lipid during sequential phases of digestion? How critical was drug association into bile salt micelles and how did this occur? What was the effect of different lipids and excipients on digestion?
To illustrate some of the issues surrounding the delivery of lipophilic drugs, Professor Charman described his research into the bioavailability of the antimalarial halofantrine. This was a highly effective agent, active against some resistant forms of Plasmodium falciparum. However, it presented less favourable pharmacokinetic characteristics. When given in its native form, halofantrine showed a low and variable bioavailability that increased four-fold if taken after meals. Low plasma concentrations resulted in sub-therapeutic dosing and the selection of resistant organisms; high plasma concentrations had been associated with QTc prolongation. Determining an accurate profile of the bioavailability of this poorly water soluble (1mg/ml) drug in Beagle dogs, Professor Charman and colleagues measured abnormally high bioavailability in the presence of food. Furthermore, there was a six-fold decrease in postprandial metabolism by CYP3A to the equipotent halofantrine metabolite (Hfm). Was it possible that there was intestinal lymph transport of halofantrine? Did micellar drug transport protect the drug from metabolic conversion?
If transported and absorbed with lipids, two separate paths could befall lipophilic drug molecules. Fats were digested and absorbed according to the length of their triglyceride chain. Small to medium chain triglycerides were absorbed directly across the enterocytes and passed to the liver through the portal vein. It was the long chain triglycerides that formed bile-salt micelles in the lumen; these then underwent dissociation and triglyceride resynthesis to form chylomicrons to be transported in the lymphatic system. How a drug was partitioned between the two types of fatty acids would largely depend on the physicochemical properties of the drug. However, Professor Charman suggested that, in view of the relatively sluggish flow rate of lymph compared with the circulation, it had been uncertain as to whether lymphatic transport could possibly be a major contributor to bioavailability.
To understand the pharmacokinetics of halofantrine, Professor Charman had initiated a programme of studies using a "triple-cannulated" dog model (allowing analysis of drug concentrations in the lymph duct, portal and systemic circulations). It was discovered that the extent of halofantrine transport in the lymphatics was in fact both "sizeable and rapid," being complete in 2.5 hours. This lymphatic transport might also explain QTc prolongation, he suggested. The effective concentration of the drug was higher in the lymph fluid (200mg/ml) than in the systemic circulation (1mg/ml) and, moreover, the lymphatic system emptied into the thoracic duct which was anatomically close to the heart. Postprandial solubilisation of halofantrine also explained the reduction in metabolism to Hfm. Lymphatic transport avoided local metabolism by enterocyte CYP3A and physically avoided first-pass hepatic metabolism.
Once in the circulation, it was also important to consider the effect of binding of lipophilic drugs to plasma lipoproteins, said Professor Charman. Currently, such interactions were not always considered, he suggested. Lipoprotein associations were independent of formulation and had an impact on the free drug fraction in the plasma. Lipoproteins themselves varied with food intake, diet, age and disease. For halofantrine, plasma drug concentrations were found to mirror the post-prandial rise in plasma triglyceride concentrations.
Concluding, Professor Charman said that a better understanding of the factors influencing the body's handling of poorly soluble compounds would lead to less empirical compound selectivity, and to rational and rapid formulation design.