PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF MEPERIDINE IN GOATS .1. PHARMACOKINETICS

Plasma and cerebrospinal fluid (CSF) pharmacokinetics of meperidine we re investigated after intramuscular (i.m.) or intravenous (i.v.) admin istration at a dose of 5 mg/kg in adult goats. After i.m. dosing, the plasma profile was best described by a one-compartment open model. In healthy (n = 16) and postoperative (n = 16) goats, the parameters were , respectively: t(max) 8.3 +/- 3.9 and 9.2 +/- 5.5 min, V-d 2.763 +/- 1.231 and 3.929 +/- 2.101 1/kg, Cl-b, 0.125 +/- 0.036 and 0.087 +/- 0. 025 1/kg/min, K-e 0.0563 +/- 0.0358 and 0.0271 +/- 0.0136 min(-1). The plasma profile was best fitted by a two-compartment open model follow ing i.v. injection. In this case, the parameters for healthy (n = 7) a nd post-operative (n = 13) goats were, respectively: V-d 5.212 +/- 1.9 92 and 5.085 +/- 2.288 1/kg, Cl-b 0.096 +/- 0.028 and 0.075 +/- 0.026 1/kg/min, beta 0.0211 +/- 0.0093 and 0.0160 +/- 0.0052 min.(-1). There were, however, a few individuals with a prolonged elimination phase. Bioavailability of i.m. meperidine was 66.5 +/- 15.8% in healthy (n = 6) goats, but much higher in postoperative (n = 10) ones at 94.6 +/- 3 0.0%. Meperidine diffused into and out of CSI; according to a first-or der rate process. The time-course of CSF drug concentration was simula ted by a biexponential function. CSF kinetic parameters of i.m. meperi dine for healthy (n = 7) and postoperative (n = 13) goats were: elimin ation rate constant (K-ef) 0.0269 +/- 0.0131 and 0.0305 +/- 0.0177 min (-1), peak CSF concentration time (T-maxf) 15.9 +/- 5.0 and 17.0 +/- 6 .9 min. For the i.v. dosed healthy (n = 6) and postoperative (n = 8) a nimals, K-ef was 0.0408 +/- 0.0107, 0.0414 +/- 0.0123 min(-1) and T-ma xf was 10.0 +/- 5.0 and 7.7 +/- 2.5 min, respectively. It was demonstr ated that an obviously lower peak concentration can be reached signifi cantly later in CSF than in plasma, and the kinetic behaviour of meper idine in plasma is different from that in the CSF, indicating meperidi ne analgesia might not be predicted by simple extrapolation from the k inetic data.