PHARMACOKINETICS AND PHARMACODYNAMICS OF THE 3 ISOMERS OF MIVACURIUM IN HEALTH, IN END-STAGE RENAL-FAILURE AND IN PATIENTS WITH IMPAIRED RENAL-FUNCTION

We have studied the pharmacokinetics of cis-trans, trans-trans and cis -cis mivacurium in nine healthy patients (creatinine clearance 66-133 ml min(-1)), in seven patients with end-stage renal failure requiring dialysis (creatinine clearance 4-11 ml min(-1)) and in seven patients with impaired renal function (creatinine clearance 32-49 ml min(-1)), during thiopenton-fentanyl-midazolam-nitrous oxide-oxygen anaesthesia. Mivacurium chloride was infused at a rate of 15 mu g kg(-1) min(-1) f or 10 min, 7.5 mu g kg(-1) min(-1) for a further 10 min, and then at a rate adjusted to maintain T1/T0 at 5%. The minimum duration of infusi on was 60 min (range 60-235 min). The plasma concentration of the thre e isomers was measured at regular intervals throughout the infusion, a nd for up to 300 min after the infusion was stopped. Compartmental ana lysis of the resulting isomer profiles was undertaken: one- and two-co mpartment models were fitted to derive clearance, volume of distributi on and terminal elimination half-life. Clearance of the cis-cis isomer was reduced significantly in the renal failure (median 2.4 (range 2.1 -2.6) ml kg(-1) min(-1)) and intermediate renal function groups (2.1 ( 2.0-2.9) ml kg(-1) min(-1)), compared with healthy patients (3.8 (2.6- 4.9) ml kg(-1) min(-1)) (P < 0.01 in each case). There was no signific ant difference, within the sample size studied, between the clearance of the cis-trans isomer, in health (106 (26-147) ml kg(-1) min(-1)), i n renal failure (80 (22-135) ml kg(-1) min(-1)) or with impaired renal function (87 (58-101) ml kg(-1) min(-1)); or of the trans-trans isome r (57 (18-79) ml kg(-1) min(-1)), (47 (16-88) ml kg(-1) min(-1)) and ( 44 (40-55) ml kg(-1) min(-1)), respectively). Clearance of each isomer correlated significantly with plasma cholinesterase activity (cis-tra ns, r = 0.55, P < 0.01; trans-trans, r = 0.62, P < 0.01), although thi s could be demonstrated only in healthy patients for the cis-cis isome r (r = 0.67, P < 0.05). There was no significant difference in the ter minal half-lives of any isomer between the groups: cis-cis, healthy (6 8 (41-204) min), renal failure (80 (55-153) min), impaired renal funct ion (101 (66-157) min); cis-trans, healthy (2.0 (1.3-4.4) min), renal failure (4.3 (2.3-7.8) min), impaired renal function (3.5 (1.4-10.4) m in; trans-trans, healthy (2.3 (1.6-8.1) min), renal failure (4.2 (2.4- 7.3) min), impaired renal function (13.4 (2.1-50) min). Volume of dist ribution was similar for each isomer in all three groups. The median i nfusion rate required to maintain T1/TO at 5% was significantly increa sed in the impaired renal function group, at 10.0 mu g kg(-1) min(-1), compared with both healthy patients (5.9 mu g kg(-1) min(-1)) and ren al failure patients (5.0 mu g kg(-1) min(-1)) (P < 0.05 in each case).