Rectal ropivacaine is absorbed proportionally to the dose, with low intraindividual variability.
OBJECTIVE
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.
Arlander
Eva
E
AstraZeneca R&D, Södertälje, Sweden. eva.arlander@astrazeneca.com
Sjövall
Jan
J
Sörstad
Jörgen
J
Norsten-Höög
Carina
C
Gustafsson
Lars L
LL
D000285:Administration, Rectal; D000328:Adult; D000577:Amides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001682:Biological Availability; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D000077212:Ropivacaine
D000577:Amides; D000779:Anesthetics, Local; D000077212:Ropivacaine