Biperiden Challenge Model in Healthy Elderly as Proof-of-Pharmacology Tool: A Randomized, Placebo-Controlled Trial.

Selective M1 muscarinic acetylcholine receptor (mAChR) agonists are being developed as symptomatic treatment for neurodegenerative and neuropsychiatric disorders that lead to cognitive dysfunction. Demonstrating cognition-enhancing effects in early-phase clinical development in healthy subjects is difficult. A challenge with the M1 mAChR antagonist biperiden could be used to demonstrate procognitive and pharmacological effects of selective M1 mAChR agonists. The aim of this study was to develop such a model. To this end, 12 healthy elderly subjects participated in a randomized, placebo-controlled, 3-way crossover study investigating tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of 2 and 4 mg biperiden. Repeated PD assessments were performed using neurocognitive tasks and electrophysiological measurements. A population PK-PD model was developed. Four milligrams of biperiden showed significant impairment of sustained attention (-2.1 percentage point in adaptive tracking [95%CI, -3.043 to -1.148], verbal memory (2-3 fewer words recalled [95%CI, -5.9 to -0.2]) and working memory (up to a 50-millisecond increase in the n-back task reaction time [95%CI, 21.854-77.882]) compared with placebo. The PK data were best fitted by a 2-compartment model and showed high interoccasion and intersubject variability. Population PK-PD analysis quantified significant concentration-effect relationships for the n-back reaction time, n-back accuracy, and adaptive tracking. In conclusion, biperiden caused M1 mAChR-related dose- and concentration-dependent temporary declines in cognitive functioning. Therefore a biperiden pharmacological challenge model can be used for proof-of-pharmacology studies and to demonstrate cognition-enhancing effects of new cholinergic compounds that are being developed.

Co-administration of Magnesium Oxide Reduces the Serum Concentration of Hydrophobic Basic Drugs in Patients Treated with Antipsychotic Drugs.

Magnesium oxide (MgO) is a widely used laxative. Because many antipsychotic drugs are lipophilic-basic-compounds, their solubility decreases with increasing pH and changes markedly as the pH of the solution approaches their pKa. It is highly important to clarify the effect of co-administration of MgO on the serum drug concentration for effective, safe, and appropriate medication therapy. However, the relationship between MgO administration and the serum concentration of antipsychotic drugs in patients with schizophrenia has not been reported. Therefore, in the present study, we investigated the effect of MgO administration on the concentration of antipsychotic drugs in the blood of patients with schizophrenia. The serum concentrations of biperiden, zotepine, and risperidone were assayed using an LC/MS system. The correlation between the daily dose of MgO and the relative-drug-concentration (rCp) in each patient was examined. As the MgO dose was increased, the risperidone concentration decreased. The correlation coefficient decreased for risperidone, zotepine, and biperiden, in the same order. To clarify the difference in the suppression potency of MgO on the three drugs, the relationship between the physical properties and the correlation coefficients of each drug was carefully examined. A strong correlation was observed between the pKa and the correlation coefficient. Patients with schizophrenia are often prescribed antipsychotic drugs, which have anticholinergic action and tend to suppress gastric acid secretion. We concluded that basic drug absorption might be suppressed due to an increase in the stomach pH following MgO administration. Therefore, MgO co-administration is better to avoid while taking antipsychotic drugs and anticholinergic drugs.

Application of a generic physiologically based pharmacokinetic model to the estimation of xenobiotic levels in human plasma.

Estimation of xenobiotic kinetics in humans frequently relies upon extrapolation from experimental data generated in animals. In an accompanying paper, we have presented a unique, generic, physiologically based pharmacokinetic model and described its application to the prediction of rat plasma pharmacokinetics from in vitro data alone. Here we demonstrate the application of the same model, parameterized for human physiology, to the estimation of plasma pharmacokinetics in humans and report a comparative evaluation against some recently published predictive methods that involve scaling from in vivo animal data. The model was parameterized through an optimization process, using a training set of in vivo data taken from the literature, and validated using a separate test set of published in vivo data. On average, the vertical divergence of the predicted plasma concentrations from the observed data, on a semilog concentration-time plot, was 0.47 log unit. For the training set, more than 80% of the predicted values of a standardized measure of the area under the concentration-time curve were within 3-fold of the observed values; over 70% of the test set predictions were within the same margin. Furthermore, in terms of predicting human clearance for the test set, the model was found to match or exceed the performance of three published interspecies scaling methods, all of which showed a distinct bias toward overprediction. We conclude that the generic physiologically based pharmacokinetic model, as a means of integrating readily determined in vitro and/or in silico data, is potentially a powerful, cost-effective tool for predicting human xenobiotic kinetics in drug discovery and risk assessment.

Pharmacokinetics of intramuscularly administered biperiden in guinea pigs challenged with soman.

Biperiden is an anticholinergic compound that has demonstrated effectiveness for treating organophosphate-induced seizure/convulsions. The plasma levels of biperiden associated with this efficacy have not yet been defined. In this study, the pharmacokinetics and tissue distribution of biperiden after intramuscular administration of 0.5 mg/kg were conducted while monitoring pharmacodynamic (electroencephalographic) data in soman-exposed guinea pigs. Overall, 59% of the animals had seizures terminated within 30 min of the biperiden administration. The mean time to seizure termination was 15.9 min. The pharmacokinetics of biperiden after i.m. administration to guinea pigs were best described by a one-compartment model with first-order absorption and elimination. The maximal plasma biperiden concentration (34.4 ng/mL) in seizure-terminated animals occurred at 26.3 min. Extensive partitioning into peripheral tissues was noted supporting the relatively large volume of distribution observed. Maximal biperiden concentrations in the cortex and brain stem were found at 30 min and were 2.3 and 1.7 times greater, respectively, than that in plasma. The time for maximal plasma concentration was found to corresponded well with the mean time to seizure termination following drug administration.

Influence of lipophilicity and lysosomal accumulation on tissue distribution kinetics of basic drugs: a physiologically based pharmacokinetic model.

This paper examines the role of lipophilicity in the tissue distribution kinetics of basic drugs. Basic drugs have a large distribution volume and are distributed widely in various tissues in the following order: lung, fat, heart, kidney, brain, gut, muscle and bone. The fat volume in the whole body influences the disposition kinetics. There is a good correlation in various tissues between the tissue-plasma concentration ratio and the octanol-water partition coefficient among various drugs. We constructed a physiologically-based pharmacokinetic model on the basis of drug lipophilicity and found that drug distribution decreased when NH4Cl was administered concomitantly. In regards to subcellular distribution, the relative specific contents of chlorpromazine, imipramine and biperiden with respect to the protein in lysosomes were 7.3, 9.6 and 4.2, respectively, while those in other subcellular organella, including mitochondria, were only 0.4-1.7, indicating preferential accumulation of these drugs in lysosomes. The uptake of basic drugs into lysosomes depended on both intralysosomal pH and drug lipophilicity. As the lipophilicity of the basic drugs increased, they accumulated more than would have been predicted from the pH-partition theory and raised the intralysosomal pH more potently, probably owing to their binding with lysosomal membranes, with or without intralysosomal aggregation. We conclude that the distribution kinetics of basic drugs is driven by drug lipophilicity and uptake into lysosomes, and these phenomena provide a possible basis for drug interaction in clinical treatments.

The determination of biperiden in plasma using gas chromatography mass spectrometry: pharmacokinetics after intramuscular administration to guinea pigs.

A gas chromatographic-mass spectrometric (GC-MS) method has been developed for the analysis of the biperiden from plasma. The method utilizes 290 microl of plasma and a simple hexane extraction/clean-up procedure. Standard curves were linear over the range of 1.9-250 ng/mL. The range of correlation coefficients for the individual standard curves was 0.9984-0.9999; the largest coefficient of variation expressed as a percentage (% CV) was 11.5%. Precision and accuracy were examined by assessing between-day and within-day variability. For between-day precision, the % CVs ranged from 2.86 to 5.17%. Accuracy as expressed by percentage error ranging from -2.16 to 5.83%. The study for within-day precision demonstrated % CVs from 0.95 to 5.55% with accuracy from -3.37 to 2.45%. Applicability of the method was demonstrated by examining the pharmacokinetics of intramuscular (i.m.) biperiden as an anticonvulsant treatment in a guinea pig model for organophosphate (OP)-induced seizure activity. Mean pharmacokinetic parameter estimates were similar to literature values; selected mean pharmacokinetic parameter estimates were: apparent volume of distribution, 13.9 L/kg; half-life of elimination, 93 min; time to maximal plasma concentration, 27.4 min; and maximal plasma concentration, 32.22 eta g/mL. The time to maximal plasma concentration was found to be similar to the onset time for terminating OP-induced seizure activity in guinea pigs receiving biperiden as an anticonvulsant treatment. The studies indicate that the method affords the required precision, accuracy and sensitivity to assay biperiden at the doses utilized for these pharmacokinetic studies after i.m. administration to guinea pigs.

Pharmacokinetic and pharmacodynamic interactions among haloperidol, carteolol hydrochloride and biperiden hydrochloride.

A beta-adrenoceptor blocker and an anticholinergic agent are often prescribed concomitantly for the treatment of neuroleptic-induced akathisia. The aim of this study was to investigate possible pharmacokinetic interactions of neuroleptic haloperidol with the beta-blocker carteolol and the anticholinergic biperiden. In a 5-step, open-labeled, oral single-dose study, eight healthy male volunteers received 2 mg haloperidol, 10 mg carteolol hydrochloride, and 2 mg biperiden hydrochloride: first each drug alone, then a combination of haloperidol and carteolol, and then all three drugs concurrently. Serum concentrations of haloperidol, carteolol, and biperiden were determined up to 24 hr postdosing, and a safety evaluation was conducted throughout the study. Carteolol increased the area under the haloperidol serum concentration-time curve (AUC0-t) 1.4-fold (P = 0.0014) and decreased the serum clearance of haloperidol up to 67% (P = 0.0127). Biperiden reduced the serum haloperidol concentrations increased by the administration of carteolol. No significant changes of the serum pharmacokinetics of carteolol and biperiden were found as a result of any drug combinations. Adverse events of the central nervous system such as sleepiness and changes in pupil size were observed, but all were mild with clinical insignificance.

Haloperidol, biperideno e parkinsonismo / Haloperidol, biperiden and parkinsonism

O autor fez uma extensa revisäo bibliográfica sobre os neurolépticos, em especial o haloperidol, bem como sobre as reaçöes extrapiramidais, com atençäo principal ao parkinsonismo, com descriçäo de quadros e tratamentos indicados

Influence of ammonium chloride on the tissue distribution of anticholinergic drugs in rats.

Ammonium chloride (NH4Cl) increases lysosomal pH and thereby abolishes intralysosomal accumulation of drugs. Its effect on the tissue distribution of biperiden and trihexyphenidyl in rats has been investigated. The tissue-plasma concentration ratios (Kp) of these drugs in various tissues were determined by infusion studies at steady-state in the presence or absence of NH4Cl. Treatment with NH4Cl reduced the Kp values for both drugs, causing the largest reduction in Kp in the lung (52.1 to 11.8 for biperiden and 59.5 to 18.9 for trihexyphenidyl; ratios of decrease 0.77 and 0.68, respectively), followed by the heart and kidneys, with relatively small reductions in the brain, gut, muscle and fat. Subcellular fractionation studies in the lung indicated that the subcellular fraction-plasma concentration ratio of each drug at the steady state (K(p,sf)) was reduced by treatment with NH4Cl, with the largest decrease in the post-nuclear fraction (ratio of decrease 0.82 for biperiden and 0.74 for trihexyphenidyl), followed by the nucleus, microsomes and supernatant, in that order. A strong correlation was found between the ratio of decrease in K(p,sf) after NH4Cl treatment and the specific activity of acid phosphatases, a marker of lysosomes, in each fraction (biperiden, r = 0.948; trihexyphenidyl, r = 0.945). These results suggest that acidic organelles contribute significantly to the distribution kinetics of anticholinergic drugs.

Effect of sequence of administration on the pharmacokinetic interaction between the anticholinergic drug biperiden and [3H]quinuclidinyl benzylate or [3H]N-methylscopolamine in rats.

In rats the pharmacokinetic interactions between the anticholinergic drug biperiden and [3H]quinuclidinyl benzylate ([3H]QNB) or [3H]N-methylscopolamine ([3H]NMS) is affected by the sequence in which the drugs are administered. Drug concentrations in various tissues were determined after intravenous administration of [3H]QNB or [3H]NMS (325 ng kg(-1)). Biperiden (6.4 mg kg(-1)) was administered either 5 min before, concomitantly with or 20 min after injection of [3H]QNB or [3H]NMS. When biperiden was administered concomitantly with or before [3H]QNB, distribution of [3H]QNB among the regions of the brain and other tissues was reduced; at 4 h the ratio of the distribution of [3H]QNB for experimental animals to that for control animals ranged from 0.15 to 0.9. When biperiden was administered after [3H]QNB, the distribution of [3H]QNB in the brain and other tissues was significantly higher than for the other two treatments (P < 0.01). However, for [3H]NMS the sequence of administration had no effect on the distribution of the drug in the brain and other tissues except for the kidney. In-vitro, in crude synaptosomal membranes, the amount of [3H]QNB at 2 h relative to the control concentration at equilibrium was 87% when biperiden was added before [3H]QNB and 56% when biperiden was added after [3H]QNB. In both instances the concentration of [3H]NMS reached equilibrium within 30 min. These findings suggest that the difference between the rate constant of association and dissociation at the possible site of action gives rise to the effect of the sequence of administration on the pharmacokinetic interaction.

Contribution of lysosomes to the subcellular distribution of basic drugs in the rat liver.

PURPOSE: We examined the subcellular distribution of the basic drugs, chlorpromazine (CPZ), imipramine (IMP) and biperiden (BP), in rat liver, and evaluated the contribution of lysosome (Lys) to their intracellular distribution in comparison with that of mitochondria (Mit). METHODS: In an in vivo distribution, the concentrations of CPZ, IMP and BP in the liver subcellular fractions were determined. In an in vitro study, uptake of [3H]IMP into Lys and Mit fractions was determined in the presence or absence of several agents. RESULTS: The distribution of these drugs 10 min after administration was quite similar. However, the relative specific contents (the drug concentration per protein of each fraction divided by that of the total homogenate) in Lys were 7.3, 9.6 and 4.2, respectively for CPZ, IMP and BP, whereas those in the other organella were only 0.4 approximately 1.7. In an in vitro uptake study, the dose response of IMP uptake into Lys was biphasic, while that into Mit fractions was monophasic. The binding of IMP to the high affinity sites of Lys was pH dependent and disappeared in 50 mM NH4Cl or 50 microM CPZ, both of which increased the intralysosomal pH, the low affinity sites were not affected by these drugs. CONCLUSIONS: The results indicated that Lys has the highest affinity for the basic drugs in the liver and that its contribution to their subcellular distribution depends on the intralysosomal pH, which is also affected by these drugs. The importance of these effects may become significant in combination therapy using various basic drugs.

Changes in functionally determined order processes of the EEG in a motor task due to various dosages of biperidene.

Animal experiments have demonstrated that the cholinergic system plays an important role in the activation of the cerebral cortex in conjunction with motor activities. In order to study the significance of the cholinergic system in the generation of voluntary movements in man, the effects of the anticholinergic drug biperidene on EEG states were analyzed. The effects depend strongly on the dosage and are shown in various frequency bands, topographic loci and time periods. Different functional significances of various frequency bands were found. In the alpha band motoric control processes are seen as an expression of mechanisms which substitute the cholinergic system. A shift of functions from the theta to the delta band with the increase of the medication seems to parallel an enhancement of motivational or volitional effort. The emergence of highly ordered EEG states is seen to be meaningful in view of the underlying processes of voluntary movements.

Pharmacokinetics of anticholinergic drugs and brain muscarinic receptor alterations in streptozotocin diabetic rats.

We studied the effects of experimental diabetes on the pharmacokinetics of biperiden (BP) and scopolamine (SP) and brain muscarinic receptor alterations in rats after the injection of streptozotocin (STZ) (60 mg kg-1 i.v.). The serum levels of BP and SP differed significantly between the rats 14 weeks after the STZ treatment and age-matched control rats. The values of total body clearance (CLtot) of BP and SP were significantly increased by STZ treatment. The values of volume of distribution (Vdss) of SP were slightly increased in the STZ-treated rats, although Vdss of BP was decreased. Because of the high lipophilicity of BP, Vdss of BP may be decreased due to the reduced fat tissue volume caused by STZ treatment. The density of the muscarinic receptors in whole brain was measured by a radioligand receptor binding assay using [3H]-quinuclidinyl-benzylate ([3H]-QNB). The density in the diabetic rats two weeks after the STZ treatment was significantly decreased compared to age-matched control rats. However in the diabetic rats 14 weeks after the STZ treatment, there was no difference in the density of muscarinic receptors. The IC50 of muscarinic antagonist for the binding of [3H]-QNB to the receptor did not change on STZ treatment. Modulation of the receptor following repeated anticholinergic drug exposure was studied. In control rats, the number of muscarinic receptors in the brain increased by 6.9% on chronic treatment with BP for two weeks. When diabetic rats were treated with BP and SP, the number of muscarinic receptors in the brain increased by 9.6% and 33.8%, respectively.

Interaction study between remoxipride and biperiden.

Twelve healthy male volunteers took part in a double-blind randomised cross-over study composed of three treatment sessions: remoxipride 100 mg; remoxipride 100 mg plus biperiden 4 mg; and biperiden 4 mg. Plasma and urine concentrations of remoxipride and biperiden, plasma prolactin levels, salivary flow and adverse events were recorded to assess pharmacodynamic interactions. Remoxipride and biperiden had no effect on each other's plasma concentrations. Biperiden did not affect the urinary recovery or renal clearance of remoxipride. Prolactin levels were unaffected by biperiden but increased following remoxipride administration. Differences in prolactin Cmax and tmax following remoxipride versus concomitant (remoxipride + biperiden) treatment were not statistically significant. However, a slight but statistically significant (P = 0.04) increase in prolactin AUC was observed after concomitant treatment. No significant differences could be observed between the recorded salivary flow in all the treatment sessions. Single doses of remoxipride and biperiden showed no pharmacokinetic or pharmacodynamic interaction.

Brain regional pharmacokinetics of biperiden in rats.

The pharmacokinetic profiles of biperiden (BP) in blood and in specific brain regions were investigated in rats after acute i.v. administration. The regional brain-to-blood unbound concentration ratios (Kpf) were also determined after 16 h intravenous infusion of BP. The Kpf values ranged from 30 to 75 in the different brain regions and showed decreasing concentrations in the following order: pons + medulla oblongata, basal ganglia, amygdala, hypothalamus, thalamus, mesencephalon, bulbus olfactorius + septum, hippocampus, frontal cortex, occipital cortex, cerebellum. The relationship between BP and acetylcholine (ACh) concentrations in the brain regions was examined. ACh levels in the various brain regions ranged from 8 to 44 ng g-1 tissue. There was a significant correlation between the Kpf values of BP and the levels of ACh in the brain regions except for the pons + oblongata. BP concentrations in the brain regions after BP administration were predicted based on the physiological pharmacokinetics. There was reasonable agreement between the model predictions and the observed data.

Potential error in the measurement of tissue to blood distribution coefficients in physiological pharmacokinetic modeling. Residual tissue blood. I. Theoretical considerations.

Physiological pharmacokinetic models require the determination of tissue to blood distribution coefficients. A theoretical model has been developed and the resulting equations indicate that under certain conditions it is necessary to correct for the presence of drug in the residual blood remaining in the tissue. The potential error in ignoring this residual blood is expressed mathematically in terms of several important factors that include the anatomical features of the tissue (volume fractions of the blood, interstitial fluid, and cellular space) as well as the physicochemical properties of the drug (extent of binding in the blood and tissues). These theoretical considerations and resulting simulations have been applied to experimental literature data for several compounds (methotrexate, digoxin, and biperiden). We conclude that correction for the residual blood is necessary when the values of tissue to blood distribution coefficients are very small or large (relative to one) and when the volume fraction of the blood in tissue is substantial.

Effect of fat tissue volume on the distribution kinetics of biperiden as a function of age in rats.

The relationship between the volume of fat tissue and variations in the time course of plasma biperiden concentration in rats has been examined in three different groups (4-, 10-, and 50-week-old rats). The plasma concentrations at 24 hr after iv injection of 3.2 mg/kg varied between 0.8 ng/ml (4-week-old rats) and 5.0 ng/ml (50-week-old rats). The rank order of the steady state distribution volume of biperiden was: 50-week-old rats greater than 10-week-old rats greater than 4-week-old rats. The fat volume of the whole body, extracted from the dried carcass with ether, varied between 42 g/kg (4-week-old rats) and 167 g/kg (50-week-old rats). There was a good correlation between the steady state distribution volume of biperiden per lean mass body weight and the fat volume per lean mass body weight (r = 0.987). The fat/plasma concentration ratios at 8 hr after the iv injection varied between 600 (4-week-old rats) and 200 (50-week-old rats), whereas the brain/plasma concentration ratios were identical to those at steady state among the three groups. The time courses of biperiden concentration in plasma, brain, and fat were simulated using a physiological pharmacokinetic model. There was reasonable agreement between the model predictions and the observed data, suggesting that the change in the fat volume is a dominant determinant of the distribution volume of biperiden in rats. Age-related changes in tissue and plasma concentrations are discussed in relation to the clinical usefulness of the blood level monitoring.

Drug interaction studies with remoxipride.

The interaction potential of remoxipride was investigated with biperiden, warfarin, diazepam, and ethanol. The studies were conducted in 12 healthy volunteers each of whom received single doses of remoxipride, the interacting drug, and the combination in a randomized crossover design. Remoxipride and biperidene had no influence on each other's pharmacokinetics. The pharmacokinetics of warfarin enantiomers were uninfluenced by remoxipride. Ethanol and diazepam had no effect on the pharmacokinetics of remoxipride. The effect of remoxipride on the elevation of plasma prolactin levels was not modified by biperiden and the effect of warfarin on the prolongation of prothrombin time was uninfluened by remoxipride. Remoxipride showed no pharmacokinetic interaction with any of the drugs studied, nor was any pharmacodynamic interaction observed in the remoxipride versus biperiden and remoxipride versus warfarin studies.