Nankervis, Richard
(1992)
The lymphatic absorption of the retinoids.
PhD thesis, University of Nottingham.
Abstract
An understanding of the criteria governing lymphatic absorption of drugs from the gastrointestinal tract may lead to selective uptake of drugs via this route. Lymphatic absorption may have potential advantages over the portal absorption of drugs; first pass elimination may be avoided as the drug reaches the systemic circulation before it reaches the liver, the absorption of some poorly absorbed drugs may be improved and it may provide a means of targeting anticancer agents directly to the lymphatics.
In the present study, the lymphatic uptake of a series of retinoids was investigated after oral administration. The most important factors which were found to affect lymphatic absorption were, the chemical nature of the compound and the nature of the oily vehicle in which the retinoid was administered.
It was found that the greater the lipophilicity of the retinoid, (as defined by the logarithm of its octanol : water partition coefficient, log. P), the greater was its lymphatic absorption. Temarotene, Ro 15-0778, (log. P = 8.7) exhibited a maximum dose adjusted lymphatic absorption rate of 4100 ng/h compared with the less lipophilic Ro 04-3780 (log. P = 6.8) which showed a maximum rate of only 150 ng/h.
The oily vehicle in which the retinoid was orally administered strongly influenced the rate of absorption via the lymphatic route. Ro 04-3780 demonstrated a 150 fold difference between the selected oils giving the maximum and the minimum lymphatic absorption rate. The best oils in this role appeared to be those in which the retinoid showed the least solubility.
Mesenteric lymph flow rate was also shown to vary depending upon the oil. Basal lymph flow rate in the fasted rat, after dosing with saline, was 1.6 m1/h/kg. Cottonseed oil and soyabean oil promoted an increase in this flow rate to greater than 3.0 ml/h/kg (p < 0.01) when orally administered with Ro 04-3780. Conversely, linoleic acid suppressed the mean lymph flow rate to 0.8 ml/h/kg (p < 0.01) after oral administration with Ro 04-3780.
Lymph turbidity was evaluated as an indication of chylomicron formation and transport in the lymph. Since the chylomicron is the particle in which dietary fats enter the lymphatic system, it was thought that lipophilic drugs, which are soluble in dietary lipid, may be carried into the lymphatic system via this pathway. The mixed long chain fatty tri-acyl glycerol oils, cotton seed oil, soyabean oil and peanut oil, when orally dosed to rats, produced the most turbid lymph (25 - 48 times greater than the turbidity produced after an oral dose of saline). These type of oil also promoted the highest lymphatic uptake rate for the retinoids. Other oils including, oleic acid, linoleic acid and MTS (a Miglyol S12 based self-emulsifying oil system), demonstrated much wider ranging extents of lymphatic absorption, but produced lymph with similar but lower turbidity (10 - 12 times greater than the turbidity produced after an oral dose of saline). A self-emulsifying oil system was developed for use in the oral administration of a retinoid. This system (MTS), produced a stable emulsion with a particle size of 500 nm after gentle mixing with an aqueous solvent and contained 80% Miglyol 812 and 20 % surfactants. MTS increased both the lymphatic and portal absorption rates for Ro 15-0778 by three fold compared with Miglyol S12 alone, improving the overall bioavailability but without selective promotion of lymphatic uptake.
The effect of feeding, prior to orally dosing with an oil (linoleic acid) containing Ro 10-9359, was to suppress greatly the portal absorption rate of the retinoid from 310 ng/h to less than 25 ng/h.
A number of factors, which were believed to be important in the lymphatic absorption of the retinoids, have been investigated here, using the rat as an animal model. The data obtained in this work suggest that lymphatic absorption is a very complex process and the factors which govern this absorptive pathway vary depending upon the nature of the drug being studied and the nature of the orally dosed vehicle.
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