| Meperidine was administrated intramuscularly or intravenously with a single dose of 5mg/kg in healthy and postoperative adult goats. A gas chromatographic (GG) procedure was used to determine the drug levels in plasma and cerebrospinal (CSF) . An averaged cerebral evoked potentials (CEP) technique was applied to measure analgesic effect of the drug. The purpose of this research is to study the pharmacokinetic characteristics of meperidine in plasma and CSF, especially to find out the relationships between effect and time and between concentration and effect of the drug by an approach of simultaneous pharmacokinetic-pharmaco-dynamic modeling.Pharmacokinetic studies of meperidine were performed in 16 healthy and 24 postoperative goats. After intramuscular (im) administrition, the plasma profiles of the drug could be described by a one-compartment model. The important kinetic parameters for healthy and postoperative goats were as follows: elimination half life time (t(?)) 15.86±8.50 and 51.06±50.60 min, the peak plasma concentration time (Tmax) 8.26±3.94 and 11.01±7.70 min, the volume of distribution (Vd): 2.7627 ± 1.2313 and 4.2679±2.6227 l/kg, respectively. The bioavail-ability of meperidine by im route was 66% in healthy goats, and was much higher as 95% in postoperative ones.After intravenous (iv) administration of meperidine in 11 healthy and 15 postoperative goats, all the plasma concentration-time data could be fitted to a two-compartment model. the important kinetic parameters were: t(?) : 93.07± 90.15 and 62.63±40.46 min, Vd: 7.4057±3.8620 and 5.6055±2.5328 l/kg respectively. This result manifested that the meperidine is absorbed and eliminated quickly with a wide distribution in goats.The kinetics of meperidine in CSF was studied. The drug diffused into and removed from CSF according to first-order rate process. The time course of CSF meperidine concentration might be simulated by a biexponential equation. The kinetics of CSF meperidine by im adminisration was investigated in 7 healthy and 14 postoperative goats. The parameters obtained were as follows: elimination half life time of CSF drug [t(?) ke(f)] 29.58±10.29 and 41.82±44.02 min, the peakCSF concentration time [Tmax(f)] 15.91 ±4.96 and 17.52 ±6.94 min, respectively. After iv administration of meperidine in 5 healthy and 8 postoperative goats, the kinetic parameters of CSF drug were as follows: t* ko(f) 17.92±4.56 and 18.18±5.83 min, Tmax(f): 10.0114.99 and 7.71+2.53 min, respectively. By comparing the corresponding kinetic parameters of meperidine in plasma and in CSF, it was found that there were significant differences of kinetic behaviour between them. The peak concentration in CSF was lower than in plasma, and the peak concentration time in CSF was also later than in plasma. This indicates that the blood-brain barrier has certain resistance to transportation of meperidine into central nervous system.The regressive estimations among plasma drug level, CSF drug level, and efficiency of drug were not quite satisfactory, although there were somewhat of parallel declining relations.A siffittltaneous pharmacokinetic-pharmacodynamic (PK-PD) modeling was established to study the effect-time and concentration-effect relations. An effect compartment linked to the plasma compartment was postulated in the model. The hypothetical amount of meperidine in effect compartment was related to the observed analgesic effect though the Hill equation, a nonlinear sigmoid maximal effect model. By fitting the measured plasma concentration-effect-time data to the PK-PD model, the following parameters were calculated. After im administration in 16 goats and iv administration of meperidine in 13 goats, the elimination rate constants of drug in effect compartment (Keo) were 0.3744+0.2546 and 0.1123 + 0.0428 min"1, the drug levels in effect compartment causing a half of maximal analgesia [ EC(B0) ] were 0.7022 ± 0.3274 and 0.4141+0.2636 ng/ml, the theoretical maximal effects (Emax) were 89.63±15.63M and 85.92+9.64M, and the Hill coefficients (s) were 2.61 ±1.21 and 2.37 + 1.15 , respectively. By using statistical analysis, it was proved that Keo , EC(S0) with im administration were markedly higher than those with iv administration;Atowever, the routes of administration had no influences on the Hill coefficient , Emax and the total amount of effect which was presented as the area under effect-time curve (AUE).It was found by practicing the PK-PD aodels that the peak effects (Emax) were 64.44+14.64% and 68.02 + 11.51M at 14.56±7.35 and 8.46±2.17 min after im and iv dosing, respectively. The total amounts of effect (AUE) were 2625±1276 and 2223±1005 min ? %, respectively. The Emax and AUE were not affected by the routes of administration. This finding suggested in clinical cases that meperidine should be given intramuscularly if it is not nessessary to obtain pain relief instantly. On the other hand , the peak effect appeared much later than the peak concentration in plasma, but simultaneously with the peak drug level in CSF after im and iv administration. A obvious hysteresis was observed between plasma concentration and its analgesic effect.The comparision of kinetic parameters, which were obtained from healthy and postoperative goats, manifested that surgical operation and muscle relaxant (tubocurarine chloride) enhanc^ absorption, bioavailability, and distribution of the drug, but prolonged the elimination process after intramuscular dosing;however, the kinetic parameters of meperidine given intravenously were not altered by the above factors. On the other hand , the operation and muscle relaxant could facilitate the diffusion of drug into CSF, and increase the peak concentration and the total amount of meperidine in CSF. Under such conditions, the changes of pharmacokinetic parameters in plasma and CSF might prolong the duration and increase the intensity of analgesic effect, and in the meanwhile, the toxicity of meperidine night be appeared.The quantitative procedures for determining the drug level and drug effect were also developed and evaluated in the studies. A sensitive and specific GC method with a internal standard of diphenhydramine was successfully used and reported here. In the meanwhile, a recording of Wave P3 , the late component of CEP which was induced by stimulating the tibial nerve of goats, was measured as pain index with a area-meter. And the intensity of analgesic effect after meperidine administration was observed by the area reduction of Wave P3 . Such a method of measuring Weve P3 is more stable, accurate, and convenient in use.
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