In-depth neuropharmacokinetic analysis of antipsychotics based on a novel approach to estimate unbound target-site concentration in CNS regions: link to spatial receptor occupancy.

The current study provides a novel in-depth assessment of the extent of antipsychotic drugs transport across the blood-brain barrier (BBB) into various brain regions, as well as across the blood-spinal cord barrier (BSCB) and the blood-cerebrospinal fluid barrier (BCSFB). This is combined with an estimation of cellular barrier transport and a systematic evaluation of nonspecific brain tissue binding. The study is based on the new Combinatory Mapping Approach (CMA), here further developed for the assessment of unbound drug neuropharmacokinetics in regions of interest (ROI), referred as CMA-ROI. We show that differences exist between regions in both BBB transport and in brain tissue binding. The most dramatic spatial differences in BBB transport were found for the P-glycoprotein substrates risperidone (5.4-fold) and paliperidone (4-fold). A higher level of transporter-mediated protection was observed in the cerebellum compared with other brain regions with a more pronounced efflux for quetiapine, risperidone and paliperidone. The highest BBB penetration was documented in the frontal cortex, striatum and hippocampus (haloperidol, olanzapine), indicating potential influx mechanisms. BSCB transport was in general characterized by more efficient efflux compared with the brain regions. Regional tissue binding was significantly different for haloperidol, clozapine, risperidone and quetiapine (maximally 1.9-fold). Spatial differences in local unbound concentrations were found to significantly influence cortical 5-HT2A receptor occupancy for risperidone and olanzapine. In conclusion, the observed regional differences in BBB penetration may potentially be important factors contributing to variations in therapeutic effect and side effect profiles among antipsychotic drugs.

Translational aspects of blood-brain barrier transport and central nervous system effects of drugs: from discovery to patients.

The development of CNS drugs is associated with high failure rates. It is postulated that too much focus has been put on BBB permeability and too little on understanding BBB transport, which is the main limiting factor in drug delivery to the brain. An integrated approach to collecting, understanding, and handling pharmacokinetic-pharmacodynamic information from early discovery stages to the clinic is therefore recommended in order to improve translation to human drug treatment.

The influence of age on the distribution of morphine and morphine-3-glucuronide across the blood-brain barrier in sheep.

BACKGROUND AND PURPOSE: The effect of age on the distribution of morphine and morphine-3-glucuronide (M3G) across the blood-brain barrier (BBB) was studied in a sheep model utilizing intracerebral microdialysis. The effect of neonatal asphyxia on brain drug distribution was also studied. EXPERIMENTAL APPROACH: Microdialysis probes were inserted into the cortex, striatum and blood of 11 lambs (127 gestation days) and six ewes. Morphine, 1 mg x kg(-1), was intravenously administered as a 10 min constant infusion. Microdialysis and blood samples were collected for up to 360 min and analysed using liquid chromatography-tandem mass spectrometry. The half-life, clearance, volume of distribution, unbound drug brain : blood distribution ratio (K(p,uu)) and unbound drug volume of distribution in brain (V(u,brain)) were estimated. KEY RESULTS: Morphine K(p,uu) was 1.19 and 1.89 for the sheep and premature lambs, respectively, indicating that active influx into the brain decreases with age. Induced asphyxia did not affect transport of morphine or M3G across the BBB. Morphine V(u,brain) measurements were higher in sheep than in premature lambs. The M3G K(p,uu) values were 0.27 and 0.17 in sheep and premature lambs, indicating a net efflux from the brain in both groups. CONCLUSIONS AND IMPLICATIONS: The morphine K(p,uu) was above unity, indicating active transport into the brain; influx was significantly higher in premature lambs than in adult sheep. These results in sheep differ from those in humans, rats, mice and pigs where a net efflux of morphine from the brain is observed.

Peripheral and central H1 histamine receptor occupancy by levocetirizine, a non-sedating antihistamine; a time course study in the guinea pig.

BACKGROUND AND PURPOSE: The H(1) receptor occupancy (H1RO) in brain is an indicator of central side effects of antihistamines. Here, we determined the kinetics of central and peripheral H1RO by levocetirizine in relation to its brain and plasma concentration, and investigated the role of the blood-brain barrier in any delay in brain H1RO. EXPERIMENTAL APPROACH: Concentration-time profiles in plasma and brain were obtained after 0.1 and 1 mg kg(-1) oral doses of levocetirizine in guinea pigs. H1RO in brain was measured ex vivo using [3H]-mepyramine and, in the periphery, by measuring the degree of inhibition of histamine-induced contractions of isolated guinea pig ileum. KEY RESULTS: The concentration-time profile of levocetirizine indicated lower levels (partition coefficient, K(p)=0.06-0.08), higher t(max) (2-4 h vs 1-1.5 h) and longer terminal half-life (4-5.6 h vs 2.1-2.8 h) in brain than plasma. The H1RO at 0.1 and 1 mg kg(-1) were 75% and 97%, respectively, at 1 hr in the periphery and, in the brain, were <20% and 28-67% respectively, at all time points studied. Brain H1RO vs plasma concentrations profile showed a delay, but not when compared to brain concentrations. CONCLUSIONS AND IMPLICATIONS: This study demonstrates an effective peripheral antihistamine effect of levocetirizine without central adverse effects at the dose close to human therapeutic dose. The slow increase in H1RO in the brain with time was caused by slow blood-brain barrier transport of levocetirizine. This demonstrates the importance of measuring time course of brain H1RO in relation to brain concentrations of drugs.

Altered brain exposure of morphine in experimental meningitis studied with microdialysis.

BACKGROUND: During pathologic conditions such as meningitis and traumatic brain injury the function of the blood-brain barrier (BBB) is disturbed. In the present study we examined the cerebral pharmacokinetic pattern of morphine in the intact brain and during experimentally induced meningitis using a pig model. Secondly, the use of intracerebral microdialysis as a potential tool for monitoring damage in the BBB by studying the pharmacokinetics of morphine is addressed. METHODS: Six pigs were studied under general anaesthesia. One occipital and two frontal microdialysis probes and one pressure transducer were inserted into the brain tissue. Another probe was placed into the jugularis interna. Morphine 1 mg kg(-1) was administered as a 10-min infusion, and morphine concentrations were then measured for 3 h. Meningitis was subsequently induced by injecting lipopoly-saccharide into the cisterna magna. When meningitis was established, the morphine experiment was repeated. RESULTS: The unbound area under the concentration-time curve (AUCu) ratio of morphine in brain to blood was 0.47 (0.19) during the control period, and 0.95 (0.20) (P < 0.001) during meningitis. The increase in the brain/blood AUCu ratio during meningitis implies decreased active efflux and increased passive diffusion of morphine over the BBB. The half-life of morphine in brain was longer than in blood during both periods, and was unaffected by meningitis. CONCLUSION: This study demonstrates that the morphine exposure to the brain is significantly increased during meningitis as compared with the control situation.

Blood-brain barrier transport and brain distribution of morphine-6-glucuronide in relation to the antinociceptive effect in rats--pharmacokinetic/pharmacodynamic modelling.

1. The objective of this study was to investigate the contribution of the blood-brain barrier (BBB) transport to the delay in antinociceptive effect of morphine-6-glucuronide (M6G), and to study the equilibration of M6G in vivo across the BBB with microdialysis measuring unbound concentrations. 2. On two consecutive days, rats received an exponential infusion of M6G for 4 h aiming at a target concentration of 3000 ng ml(-1) (6.5 microM) in blood. Concentrations of unbound M6G were determined in brain extracellular fluid (ECF) and venous blood using microdialysis and in arterial blood by regular sampling. MD probes were calibrated in vivo using retrodialysis by drug prior to drug administration. 3. The half-life of M6G was 23+/-5 min in arterial blood, 26+/-10 min in venous blood and 58+/-17 min in brain ECF (P<0.05; brain vs blood). The BBB equilibration, expressed as the unbound steady-state concentration ratio, was 0.22+/-0.09, indicating active efflux in the BBB transport of M6G. A two-compartment model best described the brain distribution of M6G. The unbound volume of distribution was 0.20+/-0.02 ml g brain(-1). The concentration-antinociceptive effect relationships exhibited a clear hysteresis, resulting in an effect delay half-life of 103 min in relation to blood concentrations and a remaining effect delay half-life of 53 min in relation to brain ECF concentrations. 4. Half the effect delay of M6G can be explained by transport across the BBB, suggesting that the remaining effect delay of 53 min is a result of drug distribution within the brain tissue or rate-limiting mechanisms at the receptor level.

Increased blood-brain barrier permeability of morphine in a patient with severe brain lesions as determined by microdialysis.

Intracerebral microdialysis was utilised to obtain information regarding how morphine is transported across the blood-brain barrier (BBB). In a patient with a severe brain injury, we measured simultaneously unbound extracellular fluid (ECF) concentrations of morphine in human brain and in subcutaneous fat tissue, which were compared to morphine levels in arterial blood. This report shows an increase in morphine levels near the trauma site in the brain compared to uninjured brain tissue. The half-life of morphine in uninjured and injured brain tissue of 178 min and 169 min, respectively, were comparable but were longer than in blood (64 min) and adipose tissue (63 min). This indicates that morphine is retained in brain tissue for a longer time than what could be expected from the blood concentration-time profile. These results show the potential of the microdialysis technique in providing new information regarding the pharmacokinetics of drug in the human brain close to the trauma site and in macroscopically intact tissue.

The use of microdialysis in CNS drug delivery studies. Pharmacokinetic perspectives and results with analgesics and antiepileptics.

Microdialysis can give simultaneous information on unbound drug concentration-time profiles in brain extracellular fluid (ECF) and blood, separating the information on blood-brain barrier (BBB) processes from confounding factors such as binding to brain tissue or proteins in blood. This makes microdialysis suitable for studies on CNS drug delivery. It is possible to quantify influx and efflux processes at the BBB in vivo, and to relate brain ECF concentrations to central drug action. The half-life in brain ECF vs. the half-life in blood gives information on rate-limiting steps in drug delivery and elimination from the CNS. Examples are given on microdialysis studies of analgesic and antiepileptic drugs.

Pharmacokinetic-pharmacodynamic modelling of morphine transport across the blood-brain barrier as a cause of the antinociceptive effect delay in rats--a microdialysis study.

PURPOSE: To quantify the contribution of distributional processes across the blood-brain barrier (BBB) to the delay in antinociceptive effect of morphine in rats. METHODS: Unbound morphine concentrations were monitored in venous blood and in brain extracellular fluid (ECF) using microdialysis (MD) and in arterial blood by regular sampling. Retrodialysis by drug was used for in vivo calibration of the MD probes. Morphine was infused (10 or 40 mg/kg) over 10 min intravenously. Nociception, measured by the electrical stimulation vocalisation method, and blood gas status were determined. RESULTS: The half-life of unbound morphine in striatum was 44 min compared to 30 min in venous and arterial blood (p<0.05). The BBB equilibration of morphine, expressed as the ratio of areas under the curve between striatum and venous blood, was less than unity (0.28+/-0.09 and 0.22+/-0.17 for 10 and 40 mg/kg), respectively, indicating active efflux of morphine across the BBB. The concentration-effect relationship exhibited a clear hysterisis with an effect delay half-life of 32 and 5 min based on arterial blood and brain ECF concentrations, respectively. CONCLUSIONS: Eighty five percent of the effect delay was caused by morphine transport across the BBB, indicating possible involvement of rate limiting mechanisms at the receptor level or distributional phenomena for the remaining effect delay of 5 min.

Modelling of the blood-brain barrier transport of morphine-3-glucuronide studied using microdialysis in the rat: involvement of probenecid-sensitive transport.

The objective of this study was to investigate the impact of probenecid on the blood-brain barrier (BBB) transport of morphine-3-glucuronide (M3G). Two groups of rats received an exponential infusion of M3G over 4 h to reach a target plasma concentration of 65 microM on two consecutive days. Probenecid was co-administered in the treatment group on day 2. Microdialysis was used to estimate unbound M3G concentrations in brain extracellular fluid (ECF) and blood. In vivo recovery of M3G was calculated with retrodialysis by drug, preceding the drug administration. The BBB transport was modelled using NONMEM. In the probenecid group, the ratio of the steady-state concentration of unbound M3G in brain ECF to that in blood was 0.08+/-0.02 in the absence and 0.16+/-0.05 in the presence of probenecid (P=0.001). In the control group, no significant difference was found in this ratio between the 2 days (0.11+/-0.05 and 0.10+/-0.02, respectively). The process that appears to be mainly influenced by probenecid is influx clearance into the brain (0.11 microl min(-1) g-brain(-1) vs 0.17 microl min(-1) g-brain(-1), in the absence vs presence of probenecid, P:<0.001). The efflux clearance was 1.15 microl min(-1) g-brain(-1). The half-life of M3G was 81+/-25 min in brain ECF vs 22+/-2 min in blood (P<0.0001). Blood pharmacokinetics was not influenced by probenecid. In conclusion, a probenecid-sensitive transport system is involved in the transport of M3G across the BBB.

The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (-/-) and mdr1a (+/+) mice.

1. The aim of this study was to investigate whether blood-brain barrier transport of morphine was affected by the absence of mdr1a-encoded P-glycoprotein (Pgp), by comparing mdr1a (-/-) mice with mdr1a (+/+) mice. 2. Mdr1a (-/-) and (+/+) mice received a constant infusion of morphine for 1, 2 or 4 h (9 nmol/min/mouse). Microdialysis was used to estimate morphine unbound concentrations in brain extracellular fluid during the 4 h infusion. Two methods of estimating in vivo recovery were used: retrodialysis with nalorphine as a calibrator, and the dynamic-no-net-flux method. 3. Retrodialysis loss of morphine and nalorphine was similar in vivo. Unbound brain extracellular fluid concentration ratios of (-/-)/(+/+) were 2.7 for retrodialysis and 3.6 for the dynamic-no-net-flux at 4 h, with corresponding total brain concentration ratios of (-/-)/(+/+) being 2.3 for retrodialysis and 2.6 for the dynamic-no-net-flux. The total concentration ratios of brain/plasma were 1.1 and 0.5 for mdr1a (-/-) and (+/+) mice, respectively. 4. No significant differences in the pharmacokinetics of the metabolite morphine-3-glucoronide were observed between (-/-) and (+/+) mice. 5. In conclusion, comparison between mdr1a (-/-) and (+/+) mice indicates that Pgp participates in regulating the amount of morphine transport across the blood-brain barrier.

Validation of a population pharmacokinetic/pharmacodynamic model for 5 alpha-reductase inhibitors.

A population pharmacokinetic/dynamic model describing the conversion of testosterone to dihydrotestosterone (DHT) by 5alpha-reductases and the irreversible inhibition of 5alpha-reductase(s) by finasteride and dutasteride was validated. The model had been developed using data from a single dose study in healthy volunteers and was validated against data from a 28-day repeat dose study in patients with benign prostatic hyperplasia. Validation was carried out by comparing results of Monte Carlo simulations to the observed data, fitting the model to the repeat dose data and comparing with previously derived parameter values, and examining individual predictions of the model for the individuals in the repeat dose study for any bias. Simulations closely predicted the outcome of the repeat dose study, estimated parameters of the pharmacodynamic modelling were generally close to within 88 to 116% of those from the original model and the individual predictions did not indicate any bias. Thus the model derived from single dose data from healthy volunteers was considered to be valid for the prediction of DHT levels in the patient population after repeated dosing of dutasteride and finasteride.

Interchangeability and predictive performance of empirical tolerance models.

Models of tolerance are commonly derived on empirical grounds, because of lack of knowledge about the mechanism of tolerance or because of the difficulty of appropriately simplifying complex physiological processes. The present study was performed to evaluate the interchangeability of tolerance models used in the literature and to address some determinants for selection of an appropriate design and data analysis strategy. Seven models were chosen (noncompetitive antagonist model, partial agonist model, reverse agonist model, direct moderator model, indirect moderator model, pool model and adaptive pool model) along with their corresponding parameter estimates, representing a wide range of empirical models. The performance of the models on various data sets was evaluated. Data were simulated from each original model and were further analysed by the other models. The effect-time course of each and every data set could be described well by at least 2 different empirical tolerance models, but no model could describe all the data sets adequately. However, all models could adequately describe at least 2 different data sets. This indicates that, without additional knowledge or assumptions, it is unlikely that reliable mechanistic information can be deduced from the mere fact that 1 (or more) of these models can describe the data. Generally, data expressing only limited tolerance can be described by a wide variety of models, whereas few models will be appropriate for data characterised by extensive tolerance. The models that gave an adequate description of a data set were selected for further study that investigated their predictive capacity based on the parameters previously determined. Predictions were made for 4 different administration schemes. The selected models gave similar predictions for the extended designs of 3 data sets for which the original study designs characterised tolerance well. For the other 4 data sets, the selected models gave disparate predictions, although the models described the original data set well. Thus, the predictive capability of a model was linked to the original study design, whereas the correlation between predictive performance and the type of model was weak or absent. Based on the results, factors of importance for the design and evaluation of studies of tolerance were identified and discussed.

The pharmacokinetic modelling of GI198745 (dutasteride), a compound with parallel linear and nonlinear elimination.

AIMS: To characterize the pharmacokinetics of the dual 5alpha-reductase inhibitor GI198745 (dutasteride) to allow for more accurate predictions of GI198745 concentrations after different dosing schedules. METHODS: In this randomized, single-blind, parallel group study, 32 healthy male volunteers received single oral doses of GI198745 ranging from 0.01 to 40 mg. Data were analysed by nonlinear mixed effects modelling using NONMEM where both linear and nonlinear pharmacokinetic models were examined. RESULTS: The time course of GI198745 serum concentrations indicated concentration dependent elimination, with the apparent half-life increasing with dose. Data were best described by a two-compartment model with first order absorption and parallel linear and nonlinear elimination pathways. Drug absorption was rapid, and was followed by a short distribution phase. A high volume of distribution (511 l) and a low linear clearance (0.58 l h(-1)) combined to give a half-life of up to 5 (1-7) weeks at high concentrations. As concentrations declined towards Km (0.96 ng ml(-1)), the proportion eliminated by the relatively rapid saturable elimination pathway, with a maximum clearance of 6.2 l h(-1), increased and the half-life reduced to about 3 days. The estimated inter individual variability for the linear clearance was high (CV = 70%). CONCLUSIONS: G1198745 pharmacokinetics are well described by a pharmacokinetic model with parallel linear and nonlinear elimination. Simulations using this model show that at daily doses of 0.1 mg the steady state drug concentrations, and the rate at which these are achieved, are mainly influenced by the nonlinear pathway, while at daily doses above 1 mg they are almost entirely influenced by the linear pathway.

Methodological aspects of the use of a calibrator in in vivo microdialysis-further development of the retrodialysis method.

PURPOSE: To investigate the performance of two alternative retrodialysis recovery methods and to describe the influence of different recoveries on the reliability in estimating unbound extracellular concentrations of morphine. METHODS: Unbound concentrations of morphine in striatum and in blood were determined by microdialysis after a 10 min i.v. infusion in freely moving rats. In vivo recovery of morphine was determined by morphine itself, retrodialysis by drug, and by the calibrator nalorphine, retrodialysis by calibrator. RESULTS: The low calibrator recovery in striatum (8.6%) resulted in large variability in the estimation of unbound extracellular concentrations when retrodialysis by calibrator was used. In blood, where the recovery was higher (36%), the variability was smaller. Also, when retrodialysis by drug was used, the variability remained low. This difference is caused by the propagation of errors in the way retrodialysis recovery is determined. Therefore, calibrator recovery values > or =20% are preferable in concentration estimations using retrodialysis by calibrator. CONCLUSIONS: When no time-dependent change in recovery is observed, retrodialysis by drug determined before the systemic administration is the best method. The calibrator is valuable as a quality control during the experiment.

Aspects on tail-flick, hot-plate and electrical stimulation tests for morphine antinociception.

The objective of this study was to compare the results of three nociceptive tests, tail-flick, hot-plate and electrical stimulation vocalisation, reflecting the responses from different sites in the CNS. A subcutaneous morphine dose (5 mg/kg) was administered to three parallel groups of rats in which the nociceptive response was measured by one of the three methods. The baseline decreased during the period of measurement for the hot-plate test, but remained stable for the other methods. The spinally mediated tail-flick response was more sensitive to the morphine effects as compared to the supraspinally mediated hot-plate and electrical stimulation vocalisation responses. The electrical stimulation vocalisation-test demonstrated more even effect-time profiles and less variability among the rats than did the tail-flick and the hot-plate methods. In the tail-flick group, 59% of the observations attained the cut-off latency at this morphine dose, leading to underestimation of the peak effect, the area under the effect curve (AUEC), and the variability among the rats. In the hot-plate group, 13% of the observations were at the cut-off latency, and 2% in the electrical stimulation vocalisation group. Different ways of presenting the data are discussed. In conclusion, the test selected for measuring the nociceptive response will influence the effect-time profile and subsequently any pharmacodynamic parameters describing it.

Morphine-3-glucuronide has a minor effect on morphine antinociception. Pharmacodynamic modeling.

The objective of this study was to quantify the influence of morphine-3-glucuronide (M3G) on the morphine antinociceptive effect (ANE) and respiratory effects in the rat. Three groups of rats were pretreated with either saline or M3G at two different rates. Morphine infusion of 10 mg/h/kg (group A) or 20 mg/h/kg (group B) was administered to each pretreatment group for 3 h. The ANE was measured by the electrical stimulation vocalization method, and blood gas parameters (pCO2, pO2, and pH) were assessed. Independent of pretreatment all groups displayed a concurrent increase in the ANE. The maximal effect diverged between pretreatments. Acute tolerance was observed, but no rebound effect was detected. To characterize the ANE, an effect compartment model and an indirect response model were selected, both capable of describing the observed features. In both models incorporation of M3G led to a better explanation of the data. On the basis of the parameters obtained in the fits, naturally occurring M3G would reduce the antinociceptive effect during a morphine infusion (plasma concentration 15 microM) by 15-20%. The exposure of M3G did not significantly change the respiratory response following the morphine treatment.

Blood-brain barrier equilibration of codeine in rats studied with microdialysis.

PURPOSE: The purpose of the study was to investigate the distribution of codeine across the blood-brain barrier (BBB) in rats by microdialysis (MD). METHODS: Rats were administered intravenous infusion of codeine in doses of (1) 10 mg/kg, (2) 20 mg/kg for 10 min, and (3) an exponential infusion for 2 h aiming at a plasma concentration of 2500 ng/ml, in a crossover design (n = 6). Microdialysis was used to determine codeine unbound concentrations in blood and brain extracellular fluid (ECF). Total brain tissue and plasma concentrations were also determined. Nalorphine was used as a calibrator for measurement of in vivo recovery. RESULTS: Relative recovery and retrodialysis loss of codeine and nalorphine were similar both in vitro and in vivo. Codeine was rapidly transported into the brain ECF with identical influx and efflux clearance across the BBB. The AUC ratios of brain to blood were 0.99 +/- 0.25 and 0.95 +/- 0.16 for Dose 1 and 2, respectively. The Css ratio of brain to blood was 1.06 +/- 0.12 for the exponential infusion. The half-lives were 25 +/- 4 min, 22 +/- 2 min in blood and 27 +/- 5 min, 25 +/- 5 min in brain for Dose 1 and Dose 2, respectively. Total brain tissue concentrations were 3.6 +/- 1.2-fold higher than the unbound concentrations in brain. Codeine was demethylated to morphine with an unbound AUCblood,morphine/AUCblood,codeine ratio of 7.7 +/- 5.1% in blood. No morphine was detected in brain MD, but total concentrations were possible to measure. CONCLUSIONS: Codeine rapidly reached a distributional equilibrium with equal unbound concentrations in blood and brain. The brain transport of codeine did not show any dose-dependency.

Delayed antinociceptive effect following morphine-6-glucuronide administration in the rat--pharmacokinetic/pharmacodynamic modelling.

This study was conducted with the aim of characterising the pharmacokinetics and pharmacodynamics of morphine-6-glucuronide (M6G), a morphine metabolite possessing agonist properties. M6G was administered to three groups of rats as either a bolus dose, a 2 h computer-controlled stepwise infusion or as two consecutive 30-min infusions given 3 h apart. Clearance and initial volume of distribution were estimated to be 27 ml/min/kg for clearance and 339 ml/kg for initial volume. Morphine could not be detected until 4 h after dosing. The antinociceptive response profile, measured using the electrical stimulation vocalisation method, showed a pronounced delay in relation to the plasma concentration profile. The peak concentrations of 12,000 ng/ml, 6270 ng/ml and 12,800 ng/ml in the bolus, the stepwise infusion and the two consecutive infusion groups gave corresponding maximal antinociceptive effects of 49%, 181% and 168%. A pharmacokinetic-pharmacodynamic model was applied to the data and the effect delay was estimated to be 1.4 h, which is considerably longer compared to morphine (0.5 h). Acute tolerance to the antinociceptive response was observed but could not be quantified due to the slowly ascending effect. Based on these results, the importance of study design for potency determination of drugs exhibiting different effect equilibration times was elucidated. Significant increases in the pCO2 levels were observed following the stepwise infusion and the two consecutive infusions. When compared to morphine, there was a tendency of a less pronounced effect on respiration by M6G.

A model for the turnover of dihydrotestosterone in the presence of the irreversible 5 alpha-reductase inhibitors GI198745 and finasteride.

OBJECTIVE: To develop a pharmacokinetic-pharmacodynamic model that characterizes the conversion of testosterone to dihydrotestosterone (DHT) by 5 alpha-reductase types 1 and 2 and the irreversible inhibition of 5 alpha-reductase by finasteride, a 5 alpha-reductase type 2 inhibitor and by GI198745 (dutasteride), a potent and specific dual 5 alpha-reductase inhibitor. METHODS: Healthy men (n = 48) received doses of 0.1 to 40 mg GI198745 (n = 4 subjects per dose), 5 mg finasteride (n = 8), or placebo (n = 8) in a parallel-group study. Plasma concentrations of GI198745, finasteride, and DHT were measured frequently up to 8 weeks after dosing. Models were fitted with mixed-effects modeling with the NONMEM program. RESULTS: The pharmacodynamics were well described with a model that accounted for the rates of DHT formation and elimination, 5 alpha-reductase turnover, relative capacity of the 2 5 alpha-reductase isozymes, and the rates of irreversible inhibition of one (finasteride) or both (GI198745) types of 5 alpha-reductase. The model indicated that type 2 5 alpha-reductase contributed approximately 80% of plasma DHT. GI198745 was about 3-fold more potent than finasteride on 5 alpha-reductase type 2. Nearly full blockade of both isozymes was achieved at doses of 10 mg or more GI198745, although the potency of this agent on 5 alpha-reductase type 1 was less than on type 2. CONCLUSIONS: A physiologically based model for the turnover and irreversible inhibition of 5 alpha-reductase and for formation and elimination of DHT described the data well. This model helps explain differences in the rates of onset and offset of effect and offers a way to determine the relative potency of the irreversible 5 alpha-reductase inhibitors.