Pharmacokinetic aspects of the onset of action of neuromuscular blocking agents.
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Anesthesia↗
Biomedical subjects
J H Proost
Publications and source records attributed to J H Proost.
Do plasma concentrations obtained from early arterial blood sampling improve pharmacokinetic/pharmacodynamic modeling?
In pharmacokinetic/pharmacodynamic (PK/PD) modeling the first blood sample is usually taken 1 to 2 min after drug administration (late sampling). Therefore, investigators have to extrapolate the plasma concentration to Time 0. Extrapolation, however, erroneously assumes instantaneous and complete mixing of drug in the central volume of distribution. We investigated whether plasma concentrations obtained from early arterial blood sampling would improve PK/PD modeling. In 14 pigs, one of five neuromuscular blocking agents (NMBAs) was administered into the right ventricle within 1 sec and arterial sampling was performed every 1.2 sec (1st min). The response of the tibialis muscle was measured mechanomyographically. The influence of inclusion of data from early arterial sampling on PK/PD modeling was determined. Furthermore, the concentrations in the effect compartment at 50% block (EC50) derived from modeling were compared to the measured concentration in plasma during a steady state 50% block. A very high peak in arterial plasma concentration was seen within 20 sec after administration of the NMBA. Extensive modeling revealed that plasma concentrations obtained from early arterial blood sampling improve PK/PD modeling. Independent of the type of modeling, the EC50 and KeO based on data sets that include early arterial blood sampling were, for all five NMBAs, significantly higher and lower respectively, than those based on data sets obtained from late sampling. Early arterial sampling shows that the mixing of the NMBA in the central volume of distribution is incomplete. A parametric PD (sigmoid Emax) model could not describe the time course of effect of the NMBAs adequately.
Animals↗
Pharmacokinetics and pharmacokinetic-dynamic relationship between rapacuronium (Org 9487) and its 3-desacetyl metabolite (Org 9488).
UNLABELLED: Rapacuronium (Org 9487) is a rapid-onset and short- to intermediate-acting muscle relaxant. Its 3-desacetyl metabolite, Org 9488, also exerts neuromuscular-blocking activity that may become apparent after prolonged maintenance of relaxation with rapacuronium. In this study, the pharmacokinetic behavior (n = 7) of this metabolite and the pharmacokinetic/pharmacodynamic (PK/PD) relationship of rapacuronium (n = 10) and Org 9488 (n = 7) were investigated in humans. Similar protocols were used for three study groups regarding the anesthetic technique, blood and urine sampling, and pharmacokinetic and PK/PD analyses. The time course of action was measured mechanomyographically using the adductor pollicis muscle. The median clearance of rapacuronium was 7.28 mL x kg(-1) x min(-1) x with an excretion fraction in the urine of 6.2%. The clearance (studied in two groups) of Org 9488 was 1.28 and 1.06 mL x kg(-1) x min(-1) with an excretion fraction in the urine of 51.9% and 53.5%, respectively. The median rate constant of transport between plasma and the biophase of rapacuronium (0.449 min(-1)) is markedly larger than that for Org 9488 (0.105 min(-1)). The modeled concentration in the biophase at 50% effect as a measure of potency is higher for rapacuronium (4.70 microg/mL) than for Org 9488 (1.83 microg/mL). The lower clearance of the metabolite will gradually prolong the time course of the neuromuscular blockade during maintenance with rapacuronium. IMPLICATIONS: We investigated the concentration-time-effect relationship of the relaxant rapacuronium and the contribution of its metabolite. Clearance, rate constant of transport between plasma and the biophase, and modeled concentration in the biophase at 50% effect of rapacuronium are consistent with its rapid onset and short to intermediate duration. The lower clearance of the metabolite will gradually prolong the time course of the neuromuscular blockade during maintenance with rapacuronium.
Adult↗
The pulmonary first-pass uptake of five nondepolarizing muscle relaxants in the pig.
BACKGROUND: It is not known whether the lungs influence the early pharmacokinetics of muscle relaxants and, if they do, whether differences in pulmonary uptake contribute to the differences in potency and/or onset time among muscle relaxants. Because the lungs are uniquely positioned, receive the entire cardiac output, have a large capillary surface area, and can temporarily store various basic drugs, the authors determined whether substantial pulmonary first-pass uptake of muscle relaxants occurs. METHODS: In 14 pigs, rocuronium, vecuronium, Org 9487, Org 7617, or d-tubocurarine were administered simultaneously with indocyanin green within 1 s into the right ventricle, and then arterial blood was sampled every 1.2 s (in the first min). The tibialis muscle response was registered mechanomyographically. RESULTS: The maximum block was 93% (68-100% [median and range]). Onset times ranged from 83 s (78-86 s) for rocuronium to 182 s (172-192 s) for d-tubocurarine. Fraction-versus-time outflow curves showed that the peak of muscle relaxants and indocyanin green occurred almost simultaneously. Pulmonary first-pass retention was negligible. The retention of muscle relaxants at 95% passage of indocyanin green was -9% (-31 to 18%). The difference in the mean transit time between muscle relaxant and indocyanin green was 1.0 (0.8 to 1.4), 0.2 (-0.8 to 0.3), 0.3 (0.2 to 0.4), 0.5 (0.2 to 1.3), and -2.2 s for rocuronium, vecuronium, Org 9487, Org 7617, and d-tubocurarine, respectively. CONCLUSIONS: There is no substantial pulmonary first-pass uptake of rocuronium, vecuronium, Org 9487, Org 7617, or d-tubocurarine in pigs. Therefore, differences in pulmonary first-pass uptake do not contribute to the differences in potency and/or onset time among muscle relaxants.
Androstanols↗
Rapid onset/offset of rapacuronium bromide explained?
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Humans↗
Do computational results depend on PC processors?
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Computers↗
Absorption kinetics of oral sotalol combined with cisapride and sublingual sotalol in healthy subjects.
AIMS: To study the absorption kinetics of sotalol following administration of different formulations. A formulation which results in fast absorption might be useful in the episodic treatment of paroxysmal supraventricular tachycardia (SVT), atrial fibrillation (Afib) or atrial flutter (Afl). METHODS: In an open randomized crossover study seven healthy male volunteers were given an intravenous infusion of 20 mg sotalol, for assessing the absolute bioavailability, an oral solution containing 80 mg sotalol, an oral solution containing both 80 mg sotalol and 20 mg cisapride and an 80 mg sotalol tablet, which was taken sublingually. RESULTS: The addition of cisapride decreased the time at which maximum serum concentrations were reached (tmax) from 2.79 (1.85-4.34) h to 1.16 (0.68-2.30) h (P=0.009) [95% CI: -2.59, -0.55] and increased the absorption rate constant (ka) from 0.49 (0.31-0.69) h(-1) to 1.26 (0.52-5.61) h(-1) (P=0.017). The absolute bioavailability of sotalol was reduced by cisapride from 1.00+/-0.15 to 0.70+/-0.26 (P=0.006), while maximum serum concentrations of both oral solutions were not significantly different. Compared with the sublingually administered tablet with a median tmax of 2.12 (0.89-3.28) h, the sotalol/cisapride oral solution gave a smaller tmax (p=0.009) [95% CI: -1.64, -0.36]. The ka of the sotalol/cisapride solution was significantly (P=0.010) larger than the ka of 0.56 (0.33-0.75) h(-1) found after sublingual administration of the tablet. CONCLUSIONS: The sotalol/cisapride oral solution might be suitable for the episodic treatment of SVT, Afib or Afl.
Administration, Oral↗
Inhibition of the enzymic degradation of suxamethonium and mivacurium increases the onset time of submaximal neuromuscular block.
BACKGROUND: The factors that influence the onset time of submaximal (<100%) neuromuscular block are not fully known. The authors hypothesized that differences in the rate of decrease in the plasma concentration result in differences in the rate of equilibration between plasma and biophase and thus in different onset times. If this hypothesis is valid, inhibition of the enzymic degradation of muscle relaxants should increase the onset time of neuromuscular block. METHODS: Twenty pigs received either suxamethonium or mivacurium. Dose finding (70% block) was done for each pig. The enzymic degradation of the muscle relaxant was randomly inhibited by selective inhibition of plasma cholinesterase activity by tetraisopropyl pyrophosphoramide (10 pigs) or was not inhibited (10 pigs). Plasma cholinesterase activities and the mechanomyographic muscle response after peroneal nerve stimulation (0.1 Hz) were measured. RESULTS: Inhibition of plasma cholinesterase activity (by 93% and 89%, respectively) increased the onset time of suxamethonium from a median of 40 s (range, 20-45 s) to 131 s (range, 114-166 s; P = 0.009) and of mivacurium from a median of 52 s (range, 40-59 s) to 105 s (range, 90-125 s; P = 0.009). Inhibition of degradation decreased the effective dose of suxamethonium that resulted in 70% depression of the initial twitch height from 900 microg/kg (range, 400-1,000 microg/kg) to 150 microg/kg (range, 135-150 microg/kg) and of mivacurium from 100 microg/kg (range, 80-150 microg/kg) to 35 microg/kg (range, 20-50 microg/kg). CONCLUSIONS: Inhibition of the enzymic degradation of suxamethonium and mivacurium increases the onset time of submaximal neuromuscular block. Therefore, pharmacokinetics influence the onset time of submaximal neuromuscular block. These results imply that to obtain an ultrashort onset time, muscle relaxants should be developed that not only have a low affinity for the receptor but also rapidly disappear from plasma.
Animals↗
Characterization of the uptake of rocuronium and digoxin in human hepatocytes: carrier specificity and comparison with in vivo data.
Mechanisms of drug transport in the liver have been investigated predominantly in rodents. Most of the in vitro drug research in the liver is performed in liver preparations of animals. The results of such experiments frequently are discussed in relation to anticipated metabolic profiles in man, but these extrapolations are often inappropriate because of large interspecies differences in drug metabolism. In the present study, the mechanisms and specificity of the uptake of the organic cation rocuronium and the cardiac glycoside digoxin were investigated in human hepatocytes and were compared with results obtained in rat hepatocytes. The extraction ratio for the intact liver was calculated from the measured uptake rates of the compounds in the human cells in vitro and compared with published in vivo data. The initial hepatic extraction ratio, calculated from the in vitro uptake data for digoxin and rocuronium, very well reflected the initial extraction ratio for distribution in the liver in vivo in man. Uptake of 100 microM rocuronium was inhibited by 40 microM K-strophantoside (80% inhibition), and although not significantly, by 160 microM procainamide ethobromide, whereas no inhibitory effect was found in the presence of 160 microM taurocholic acid. In a previous study in rat hepatocytes, marked inhibition of digoxin uptake by quinine and only minimal inhibition by the diastereomer quinidine was demonstrated, showing clear stereoselectivity in transport inhibition. Unexpectedly, the uptake of digoxin in human hepatocytes was not inhibited significantly by quinidine or quinine, which indicates clear species differences. This is the first study to investigate the uptake mechanisms of organic cations and cardiac glycosides in human hepatocytes in some detail. The results show that uptake characteristics of drugs found in rats can not be extrapolated directly to humans.
Androstanols↗
Comparison of vecuronium with ORG 9487 and their interaction.
PURPOSE: To compare the pharmacodynamic behaviour of vecuronium with that of ORG 9487, we measured the time-course of action of equipotent doses of ORG 9487 and vecuronium and investigated their mutual interaction when given in succession. METHODS: Sixty ASA I-II patients were anaesthetized with thiopentone, fentanyl, halothane and nitrous oxide and assigned randomly to four groups. Each patient received an initial dose (ID) of either vecuronium (V) or ORG 9487 (O) followed by maintenance doses (MDn) of either V or O (ID/MD: O/O, V/O, O/V, and V/V). The time course of action was measured mechanomyographically, determining the duration until 25% recovery of the single twitch (DUR25). RESULTS: The onset time of an ID of ORG 9487 was shorter than that of an ID of vecuronium (96 vs 203 sec, P < 0.001). The DUR25 of the ID of ORG 9487 was less than half that of vecuronium (10.7 +/- 2.8 vs 28.8 +/- 6.1 min, P < 0.001). The DUR25 of MD1 and MD2 of ORG 9487 were shorter than those of vecuronium (O/O: 7.3 +/- 2.8 and 8.5 +/- 2.4 min; V/O: 12.7 +/- 3.3 and 11.5 +/- 3.5 min, vs O/V: 16.4 +/- 4.5 and 20.6 +/- 4.7 min; V/V: 18.8 +/- 3.0 and 20.1 +/- 3.8 min, respectively, P < 0.05). AN ID of vecuronium prolonged the DUR25 of MD1 and MD2 of ORG 9487 (P < 0.05). CONCLUSION: ORG 9487 is a muscle relaxant with a shorter duration of action than vecuronium. Maintenance doses of ORG 9487 are also shorter acting than roughly equipotent maintenance doses of vecuronium, irrespective of which relaxant is given initially.
Adolescent↗
Pharmacokinetics and anti-HIV-1 efficacy of negatively charged human serum albumins in mice.
Negatively charged albumins (NCAs, with the prototypes succinylated human serum albumin (Suc-HSA) and aconitylated human serum albumin (Aco-HSA)), modified proteins with a potent anti-human immunodeficiency virus type 1 (anti-HIV-1) activity in vitro, were studied for their pharmacokinetic behaviour in mice and their in vivo anti-HIV-1 efficacy in an HIV-1 infection model in mice. In contrast to the saturation kinetics found in rats, intravenous injections of 10-300 mg/kg for both NCAs showed a linear correlation between the area under the curve (AUC) and the dose. The elimination t1/2 was 25 and 30 min for Suc-HSA and Aco-HSA, respectively. Preinjections of an excess of formaldehyde-treated albumin (Form-HSA) resulted in plasma levels that were 3- and 4-fold higher for Aco-HSA and Suc-HSA, respectively. These data indicate that elimination is at least partly (scavenger) receptor-mediated. Organ distribution studies 10 min after injection showed an accumulation in liver (Suc-HSA 17.3 +/- 6.6% of the dose; Aco-HSA 20.9 +/- 2.3%) and lungs (Suc-HSA 12.7 +/- 10.5%; Aco-HSA 16.0 +/- 13.6). Intraperitoneal injection of 300 mg/kg Suc-HSA resulted in a final bioavailability of about 0.45. Suc-HSA was also evaluated for its in vivo neutralizing capacity in a human-to-mouse chimeric model for HIV-1 infection. Intraperitoneal injections of 300 and 3 mg/kg Suc-HSA, given 15-30 min before the mice were challenged with the virus, sufficed to protect these mice against infection with the HIV-1 IIIB strain.
Animals↗
Pharmacodynamics and pharmacokinetics of rocuronium in intensive care patients.
We have studied dose requirements, recovery times and pharmacokinetics of rocuronium in 32 intensive care patients. After an initial dose of 50 mg, rocuronium was administered as maintenance doses of 25 mg whenever two responses to train-of-four (TOF) stimulation reappeared (bolus group; n = 27) or by continuous infusion to maintain one response in the TOF (infusion group; n = 5). Median requirements for rocuronium were 27.4 (range 14.5-68.3) mg h-1 and 43.7 (30.9-50.3) mg h-1 in patients in the bolus and infusion groups, respectively. Median total duration of rocuronium administration was 29.0 (12.4-95.5) h and 63.4 (24.0-140.3) h, respectively. Median time from administration of the last bolus dose and end of infusion to recovery of the fourth twitch in the TOF was 100 (45-300) min and 60 (15-155) min, respectively. Arterial blood samples were obtained for up to 10 h after cessation of rocuronium administration, and concentrations of the parent compound and its putative metabolites were measured using high pressure liquid chromatography (HPLC). The plasma concentration profile (n = 12) was described adequately by a two-compartment model. Mean plasma clearance (Cl), steady-state distribution volume (Vss), mean residence time (MRT) and elimination half-life (T1/2 beta) were 3.16 (SD 1.15) ml kg-1 min-1, 769 (334) ml kg-1, 262 (120) min and 337 (163) min, respectively. Recovery times, Vss, MRT, and T1/2 beta differed from previously published data obtained after rocuronium infusion of moderate duration in surgical patients.
Adolescent↗
Pharmacokinetics and pharmacokinetic-dynamic modelling of rocuronium in infants and children.
We have determined the pharmacokinetics and pharmacokinetic-pharmacodynamic relationship of rocuronium in infants and children. We studied infants (n = 5, 0.1-0.8 yr) and children (n = 5, 2.3-8 yr), ASA II, in the ICU while undergoing artificial ventilation under i.v. anaesthesia with an arterial cannula in situ and the EMG of the adductor pollicis muscle was monitored. Rocuronium 0.06 (infants) and 0.09 (children) mg kg-1 min-1 was given i.v. over +/- 5 min until 85% neuromuscular block was obtained. Arterial blood samples were obtained over 240 min. Plasma concentrations were measured by HPLC. Pharmacokinetic-dynamic variables were calculated using the Sheiner model and the Hill equation. Statistical analysis was performed using the Mann-Whitney U test (P < 0.05). The mean administered dose was 0.32 (SD 0.08) mg kg-1 and 0.4 (0.1) mg kg-1 for infants and children, respectively. Infants differed from children in plasma clearance (4.2 (0.4) vs 6.7 (1.1) ml min-1 kg-1), distribution volume at steady state (231 (32) vs 165 (44) ml kg-1), mean residence time (56 (10) vs 26 (9) min), concentration in the effect compartment at 50% block (1.2 (0.4) vs 1.7 (0.4) mg litre-1) and the slope of the concentration-effect relationship (5.7 (1.3) vs 3.9 (0.5)). Calculated mean ED90 values were 0.26 and 0.34 mg kg-1 for infants and children, respectively. The time course of neuromuscular block after equipotent doses did not differ.
Aging↗
Relationship between chemical structure and physicochemical properties of series of bulky organic cations and their hepatic uptake and biliary excretion rates.
To obtain more insight in the relationship between physicochemical properties of cationic drugs and their hepatobiliary transport rate, a series of 12 aminosteroidal neuromuscular blocking agents (NMBAs), supplemented with data of four related NMBAs from the literature, were investigated in the isolated perfused rat liver. A significant correlation was found between plasma protein binding and the partition coefficient octanol/Krebs (log P), confirming results from the literature with other organic cations. Evidence was found for a saturable hepatic uptake of several NMBAs, indicating that carrier-mediated uptake processes are involved. Hepatic uptake rate was closely related to the lipophilicity of the compounds; the initial extraction ratio, the apparent clearance and the intrinsic clearance were significantly correlated to log P. We did not find a significant correlation between biliary clearance and lipophilicity in the current series of compounds. Pharmacokinetics analysis of perfusate disappearance and biliary excretion data revealed that a considerable fraction of the dose of these bulky organic cations is stored in the liver and seems to not be directly available for biliary excretion. This finding is in line with earlier observations showing a pronounced accumulation of this type of compounds in mitochondria and lysosomes.
Animals↗
An extended pharmacokinetic/pharmacodynamic model describing quantitatively the influence of plasma protein binding, tissue binding, and receptor binding on the potency and time course of action of drugs.
An extended pharmacokinetic/pharmacodynamic (PK/PD) model is presented, in which the effect of binding of the drug to plasma proteins and to tissue binding sites in a peripheral compartment, and nonspecific and receptor binding in the effect compartment are taken into account. It represents an extension of the classical Sheiner model, and the model proposed by Donati and Meistelman. The present model is characterized by the following parameters: Kue (exit rate constant of unbound drug from the effect compartment), Pue (ratio of the unbound clearances to and from the effect compartment), fue (fraction of drug in effect compartment that is not bound to nonspecific binding sites), Kd (equilibrium dissociation constant of drug-receptor binding), and Rtot (concentration of receptor binding sites in effect compartment). The rate of association and dissociation of the drug-receptor complex can be incorporated in the model. The influence of the pharmacokinetic parameters (V1, V2, fu, fu2, CLu10, CLu20, CLu12, CLu21) and the PK/PD model parameters (kue, Pue, fue, Kd, Rtot) on various dynamic parameters is analyzed. These include potency (single dose needed to produce 90% effect, ED90), constant infusion dosing rate needed to maintain a constant effect of 90%, time to maximum effect (onset time), and duration to 90% recovery. The neuromuscular blocking agent vecuronium is used as an example. It is shown that both potency and time course of action are strongly dependent on the ratio V1/fu, CLu10, kue, Pue (at equipotent doses the time course is not affected by Pue), fue, Kd, and Rtot (only if Rtot is high), whereas they are less affected by the ratio V2/fu2, CLu20, CLu12, and CLu21. In general, the model parameters affect the ED90 and the time course of action in the same direction, e.g., an increase of V1 results in an increase of ED90 and an increase of onset time and duration. However, the unbound clearance CLu10, the intercompartmental unbound clearance CLu12 and the receptor affinity Kd have an opposite effect on ED90 and the time course parameters, e.g., an increase of CLu10 results in an increase of ED90 and a decrease of onset time and duration. This effect may be responsible for the inverse relationship between onset time and potency of neuromuscular blocking drugs observed in animal experiments and clinical studies. We demonstrate that PK/PD analysis using the traditional effect compartment model (Sheiner model) results in an apparent value of keo, which is a function of kue, fue, Kd, Rtot, as well as the unbound drug concentration in the effect compartment Cue. On the other hand, the model proposed by Donati and Meistelman gives correct values of keo (equal to the product fue.kue), but the receptor affinity Kd and the receptor density Rtot obtained by this method are apparent values, which depend on fu, fue, and Pue.
Blood Proteins↗
Pharmacokinetics of rocuronium after bolus and continuous infusion during halothane anaesthesia.
We have studied the pharmacokinetics of a single bolus of rocuronium (Org 9426), followed by an infusion, in eight patients during anaesthesia with halothane and nitrous oxide in oxygen. Neuromuscular block was monitored using train-of-four (TOF) stimulation and recording the force of contraction of the adductor pollicis muscle. Rocuronium was administered as an initial bolus dose of 0.45 mg kg-1 followed by an infusion adjusted manually to maintain T1 (first response in the TOF) at 10% of control. Mean onset time and time to recovery of T1 to 10% were 72 (SD 19.6) s and 27 (9.6) min, respectively. The infusion rates were stable in 19.8 (6.5) min. The mean requirement for rocuronium for steady state 90% block of T1 was 528 (163.3) micrograms kg-1 h-1. After cessation of surgery the infusion was stopped and patients were allowed to recover spontaneously. The times to attain a T1 of 90% and a TOF ratio of 0.7 were 31 (11.7) min and 36 (7.3) min, respectively. Blood samples were collected for 390 min after cessation of infusion and concentrations of rocuronium and its putative metabolites measured using HPLC. A two-exponential equation was used to describe the pharmacokinetic data. The rate of clearance, mean residence time and volume of distribution at steady state were 3.3 (0.77) ml kg-1 min-1, 67.2 (18.8) min and 212.5 (40.1) ml kg-1, respectively. The distribution (T1/2 alpha) and elimination (T1/2 beta) half-lives were 7.5 (3.33) min and 85.6 (18.4) min, respectively. These values were not significantly different from previously published data for a single bolus dose of rocuronium.
Adolescent↗
Pharmacokinetics and pharmacodynamics of rocuronium at the vocal cords and the adductor pollicis in humans.
The pharmacokinetic-pharmacodynamic relationship of rocuronium at the laryngeal adductor muscles and the adductor pollicis was determined in eight patients during general anesthesia. Rocuronium was administered as an infusion at a rate of 100 micrograms.kg-1.min-1 over 5 minutes. The half-life of transport between plasma and biophase (effect compartment) was significantly shorter at the adductor laryngeal muscles (2.7 +/- 0.6 minutes, mean +/- SD) than at the adductor pollicis (4.4 +/- 1.5 minutes, p = 0.003). The concentration in the effect compartment producing 50% of the maximum effect was significantly greater at the adductor laryngeal muscles (1424 +/- 148 micrograms.L-1) than at the adductor pollicis (823 +/- 157 micrograms.L-1, p = 0.0001). The shorter onset of neuromuscular blockade at the laryngeal muscles than at the adductor pollicis may be explained by a faster transfer rate at the laryngeal adductor muscles neuromuscular junction than at the adductor pollicis neuromuscular junction.
Adult↗
Structure-pharmacodynamic-pharmacokinetic relationships of steroidal neuromuscular blocking agents.
Several new steroidal non-depolarizing muscle relaxants have been synthesized and tested in humans recently. Results from these studies suggest that the differences in time-course of action between these compounds are mainly, if not totally, related to differences in biodisposition. Biodisposition, in turn, is determined largely by the physico-chemical characteristics of the drug, such as degree of lipophilicity and protein binding. The various pharmacodynamic and pharmacokinetic variables of a series of structurally related steroidal relaxants, varying in the ester substituent at the 17th position of the androstane skeleton, have been related to the degree of lipophilicity. Significant positive relationships could be shown between lipophilicity (logP at pH 7.4) and, among other things, potency (ED90), effective concentration (EC50), unbound plasma clearance (CLupl) and rate constant of transport between plasma and biophase (ke0). The aforementioned relationships between lipophilicity and pharmacokinetic variables resulted in significant inverse relationships between lipophilicity and time course parameters, such as onset time and duration of neuromuscular blocking effects. It is concluded that changes in the molecular structure of steroidal relaxants which enhance lipophilicity coincide with a decrease of (intrinsic) potency and a shorter time course of action. Protein binding appears to be of minor importance for the biodisposition and time course characteristics, since there were only small differences in degree of protein binding between most of the investigated compounds. However, the surprisingly fast initial rate of block development observed with rocuronium may in part result from its relatively high unbound fraction in plasma.
Adolescent↗