Comparative pharmacokinetics and bioavailability of brimonidine following ocular and dermal administration of brimonidine tartrate ophthalmic solution and gel in patients with moderate-to-severe facial erythema associated with rosacea.

BACKGROUND: Persistent facial erythema is the most common primary pathological feature of rosacea, the only treatment for which is brimonidine tartrate (BT) gel. OBJECTIVES: To assess the relative bioavailability of topical BT gel in comparison with the ophthalmic BT solution. METHODS: A pharmacokinetic study was conducted to compare intraindividual systemic exposures after dermal application of BT gel (0·07%, 0·18% and 0·5%) under maximal use conditions in patients with moderate-to-severe facial erythema associated with rosacea, and administration of BT ophthalmic solution 0·2%. RESULTS: Patients who received BT ophthalmic solution 0·2% three times a day for 1 day had a mean Cmax of 54 ± 28 pg mL(-1) and a mean 0-24-h area under the curve (AUC0-24 h ) of 568 ± 277 pg h mL(-1) . Topical application of BT gel for 29 days resulted in quantifiable systemic exposure in 22%, 48%, 71% and 79% of patients who received BT gel 0·07% twice daily, 0·18% once daily, 0·18% twice daily and 0·5% once daily, respectively. The mean Cmax values for the BT gels ranged between 13 and 25 pg mL(-1) , and mean AUC0-24 h values ranged between 42 and 290 pg h mL(-1) . Systemic exposure increased with applied dose, with no drug accumulation for the duration of treatment. The systemic exposure observed with the highest dose of BT gel (0·5% once daily) was significantly lower than the systemic levels observed for the ophthalmic solution. 0·2% apply for all the concentrations. CONCLUSIONS: The systemic safety profile of BT gel may be considered better than that of the ophthalmic solution.

The roles of P-glycoprotein and intracellular metabolism in the intestinal absorption of methadone: in vitro studies using the rat everted intestinal sac.

Methadone is used as a treatment for opiate detoxification in methadone maintenance programs. Intra- and inter-patient variations in methadone bioavailability have been observed after oral methadone treatment and this makes it difficult to predict a dosing regimen. Intestinal absorption and metabolism could explain these variations. The in vitro gut sac model was used to study the intestinal absorption of methadone, and it confirmed that methadone is a substrate for P-glycoprotein. The transport of methadone was increased in presence of P-gp inhibitors verapamil and quinidine. The appearance of a major metabolite of methadone, 2-ethylidene-1, 5-dimethyl-3, 3-diphenyl pyrrolidine (EDDP) in the gut sac contents also demonstrated the existence of intestinal metabolism of methadone.

Blood and cerebral concentrations of the new potential analgesic UP 26-91 measured in vivo by microdialysis after toxic doses.

The concept of proportionality between the pharmacological effects of drugs and their dosage has been questioned since the discovery of saturable phenomenon for some drug dispositions, either during their absorption or their elimination. Such saturation may also occur during the distribution phase in the tissues. This phenomenon, however, is often difficult to demonstrate and microdialysis is a powerful technique to assess precise changes in drug concentrations in tissue. This technique has been used to compare brain and blood concentrations of a potential analgesic, UP 26-91 (3-¿[2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl]thio¿ -1,2,4-triazolo[4,3-a]pyrioline, citrate salt, CAS 115762-17-9 for the base), at different intravenous doses. Microdialysis probes were surgically implanted in the cerebral cortex and the jugular vein of male Sprague-Dawley rats (about 350 g). A single dose of radiolabelled 14(C) UP 26-91 mixed with unlabelled drug was injected into the animal's tail vein. Three doses of drug (2.5, 12.5 and 22.5 mg.kg-1) were tested, with three rats for each dose. All the doses consisted of the same amount of radiolabelled product, used as a tracer, supplemented by the amount of non-radiolabelled UP 26-91 necessary to reach the desired concentration. The rats were conscious, freely moving and had free access to food and water. Microdialysis samples were collected at the rate of 1 microliter.min-1, and sampled every 15 min for 16-17 h. The two highest doses were in the range of those used for toxicological studies. Blood UP 26-91 radioactivity concentrations were superimposable independent of the dose. Thus, it can be concluded that there was a linear relationship between blood concentrations and administered doses. By contrast, the brain concentration for the highest administered dose was statistically higher than the two others (p < 0.05), which demonstrated that UP 26-91 exhibited a non-linear pharmacokinetics in the brain. It is therefore likely that a saturable transport mechanism occurs across the blood-brain barrier. This study demonstrates that blood toxicokinetics may not correctly reflect tissue exposure to a drug.