Abstract
AIMS: This study investigated the absorption characteristics and the tolerability of rectally administered ropivacaine, a local anaesthetic, intended as a new local therapy for ulcerative colitis. METHODS: Thirty-two healthy volunteers participated in a randomized, placebo-controlled study. In study phase 1 (n = 16, double-blind, crossover) single rectal doses of ropivacaine corresponding to 50, 100 and 200 mg base were given as 20-ml gel enemas. Eight of these subjects also received an i.v. infusion corresponding to 20 mg (2H3)ropivacaine base given with the last rectal dose. In study phase 2 (n = 16, single-blind, crossover) the same rectal doses were given but formulated in 20, 40 and 80 ml gel, respectively. Peripheral venous plasma samples and urine were collected over 12 h after dosing and analysed for ropivacaine base by gas chromatography and (2H3)ropivacaine by gas chromatography-mass spectrometry. Ropivacaine and metabolites were analysed in urine by reversed phase liquid chromatography. RESULTS: AUC was proportional to the dose with a point estimate [95% confidence interval (CI)] for the increase, after doubling the dose, of 1.91 (1.66-2.20) and 1.95 (1.78-2.13) in study phases 1 and 2, respectively. The increase in Cmax was also proportional to the dose with corresponding results of 1.76 (1.52-2.04) and 1.84 (1.70-1.99). The volume of the rectal formulation had no influence on either the extent or the time course of absorption. The mean (s.d.) absolute bioavailability (%F) was 56 (18)%. AUC and Cmax showed a two- to three-fold lower intra- than interindividual variability. Zero-order kinetics dominated the first 4 h of the absorption phase. Thereafter first-order kinetics were observed. The terminal half-lives were similar between the rectal doses and were longer than that after the i.v. administration, indicating an absorption-dependent half-life. The main urinary metabolite was 3-hydroxyropivacaine corresponding to about 23% of the dose. The subjects had no difficulties in retaining the doses and rectal administration of ropivacaine was well tolerated, both locally and systemically. CONCLUSIONS: Plasma drug concentrations were proportional to the dose after rectally administered doses corresponding to 50-200 mg ropivacaine base in a gel formulation. The drug was well-tolerated. Mean bioavailability was about 60% and not influenced by variations in the enema volume. Initial absorption seemed to follow zero-order kinetics and then first-order kinetics after about 4 h. Cmax and AUC showed considerably less intra- compared with inter-individual variability, resulting in more consistent plasma concentrations within subjects.