Comparative uptake and translocation of pharmaceutical and personal care products (PPCPs) by common vegetables.

Reuse of treated wastewater to irrigate agricultural crops is increasing in many arid and semi-arid areas around the world. The presence of numerous pharmaceutical and personal care products (PPCPs) in treated wastewater and their potential transfer into food produce such as vegetables poses an unknown human health risk. The goal of this study was to identify PPCPs that have a comparatively high potential for plant uptake and translocation. A total of 20 frequently-occurring PPCPs were compared for their accumulation into four staple vegetables (lettuce, spinach, cucumber, and pepper) grown in nutrient solutions containing PPCPs at 0.5 or 5µgL(-1). Triclocarban, fluoxetine, triclosan, and diazepam were found at high levels in roots, while meprobamate, primidone, carbamazepine, dilantin, and diuron exhibited more active translocation from roots to leaves. Root uptake of neutral PPCPs was positively correlated with the pH adjusted log Kow(i.e., log Dow), and was likely driven by chemical adsorption onto the root surfaces. In contrast, translocation from roots to leaves was negatively related to log Dow, suggesting hydrophilicity-regulated transport via xylems. Compounds preferentially sorbed to roots should be further evaluated for their uptake in tuber vegetables (e.g., carrot, radish) under field conditions, while those easily translocated into leaves (e.g., carbamazepine, dilantin) merit focused consideration for leafy and other vegetables (e.g., lettuce, cucumber). However, estimation of dietary intake by humans suggested the implied risks from exposure to PPCPs via wastewater irrigation to be negligible.

Prediction of adsorption from multicomponent solutions by activated carbon using single-solute parameters. Part II--Proposed equation.

Prediction of multicomponent adsorption is still one of the most challenging problems in the adsorption field. Many models have been proposed and employed to obtain multicomponent isotherms from single-component equilibrium data. However, most of these models were based on either unrealistic assumptions or on empirical equations with no apparent definition. The purpose of this investigation was to develop a multicomponent adsorption model based on a thermodynamically consistent equation, and to validate that model using experimental data. Three barbiturates--phenobarbital, mephobarbital, and primidone--were combined to form a ternary system. The adsorption of these barbiturates from simulated intestinal fluid (without pancreatin) by activated carbon was studied using the rotating bottle method. The concentrations, both before and after the attainment of equilibrium, were determined with a high-performance liquid chromatography system employing a reversed-phase column. The proposed equation and the competitive Langmuir-like equation were both fit to the data. A very good correlation was obtained between the experimental data and the calculated data using the proposed equation. The results obtained from the original competitive Langmuir-like model were less satisfactory. These results suggest that the proposed equation can successfully predict the trisolute isotherms of the barbituric acid derivatives employed in this study.

Primidone-loaded poly-epsilon-caprolactone nanocapsules: incorporation efficiency and in vitro release profiles.

This paper describes the preparation of primidone-loaded poly-epsilon-caprolactone nanocapsules according to the interfacial deposition technique. The colloidal suspension obtained showed a monomodal size distribution with a mean diameter ranging from 308 to 352 nm. By adjusting the process parameters, the encapsulation efficiency was about 74% with good reproducibility. Primidone release from the nanocapsules was found to be slower as compared to the oily control solution despite an important burst-effect. The release profile was not influenced by the pH of the release medium.

Blood and cerebrospinal fluid pharmacokinetics of primidone and its primary pharmacologically active metabolites, phenobarbital and phenylethylmalonamide in the rat.

Primidone is a clinically useful antiepileptic drug that is metabolised to two pharmacologically active metabolites phenobarbital and phenylethylmalonamide. As data on the inter-relationship between the systemic and central nervous system pharmacokinetics of primidone and its metabolites are sparse, we have investigated their temporal inter-relationship using a freely behaving rat model which allows repeated sampling of blood (100 microl) and cerebrospinal fluid (CSF; 20 microl). After administration, by intraperitoneal injection (50, 100 or 200 mg/kg), primidone rapidly appeared in both serum (Tmax mean range 1.5-2.5 h) and CSF (Tmax mean range 2.0-3.5 h), suggesting ready penetration of the blood-brain-barrier. This was also the case for phenylethylmalonamide and phenobarbital but peak concentration occurred later. Primidone, phenylethylmalonamide and phenobarbital concentrations rose linearly and dose-dependently in both serum and CSF. The mean free fraction (free/total concentration ratio) for primidone, phenylethylmalonamide and phenobarbital was 0.86, 0.97 and 0.88, respectively, and, as their respective mean CSF/serum ratio values were 0.73, 1.06 and 0.65, it would suggest that equilibration between the blood and CSF compartments is rapid. CSF mean t(1/2) values for primidone, phenylethylmalonamide and phenobarbital were similar to those of sera and essentially paralleled the pattern seen in sera.

Adsorption of drugs onto a poly(acrylic acid) grafted cation-exchange membrane.

The influence of pH, ionic strength and the concentration of albumin in the adsorption medium as well as the charge and lipophilicity of a model drug on their adsorption onto poly(acrylic acid) grafted poly(vinylidene fluoride) (PAA-PVDF) membranes was evaluated. The PAA-PVDF membrane is a responsive porous polymer membrane that we have studied for controlled drug delivery. Sodium salicylate (anionic), flunitrazepam (neutral), primidone (neutral), desipramine (cationic) and thioridazine (cationic) were used as model drugs. The extent of drug adsorption was dependent on pH. Drug adsorption was enhanced by the dissociation of the grafted PAA chains and by a positive charge and a high lipophilicity of the drug. Increasing the ionic strength of the medium retarded the adsorption of the cationic drugs. Interestingly, the present results showing that drugs are adsorbed onto the membrane while albumin is not adsorbed onto the membrane suggest that the PAA-PVDF membrane may be suitable for separating drugs from proteinaceous substances for subsequent monitoring and evaluation.

Lack of in vivo/in vitro correlations for 50 mg and 250 mg primidone tablets.

PURPOSE: To determine if large differences in the in vitro dissolution profiles for primidone tablets would result in significant bioavailability differences. METHODS: Two separate bioavailability studies were conducted. The first study used 18 healthy subjects and compared the bioavailability of an old 50 mg tablet formulation, a new 50 mg tablet formulation, and a suspension containing 50 mg/ml of primidone. The second study enrolled 24 subjects who were to receive a new 250 mg tablet formulation, two lots of an old 250 mg tablet formulation and a 250 mg tablet from a second manufacturer. In vitro dissolution was conducted over 90 minutes, using USP 23 Apparatus 2 at 50 rpm, with 900 ml of water. RESULTS: Dissolution at 90 minutes for the old and new 50 mg tablets was approximately 20% and 100%, respectively. The dissolution of the four 250 mg tablets ranged from approximately 30% to 100%. The 50 mg tablet that dissolved slower had a longer Tmax and a 14% lower Cmax than the more rapidly dissolving tablet, but the AUC(0-infinity) values differed by only 3%. Only nine subjects completed the 250 mg study because of side effects. The differences in Cmax and AUC(0-infinity) among the four 250 mg tablets were less than 7%. CONCLUSIONS: Even though there were large differences in the in vitro dissolution of the 50 mg and the 250 mg primidone tablets, the two 50 mg tablets were shown to be bioequivalent, as were the four 250 mg tablets.

Physiologically based pharmacokinetics model of primidone and its metabolites phenobarbital and phenylethylmalonamide in humans, rats, and mice.

Physiologically based pharmacokinetic modeling of the parent chemical primidone and its two metabolites phenobarbital and phenylethylmalonamide (PEMA) was applied to investigate the differences of primidone metabolism among humans, rats, and mice. The model simulated previously published pharmacokinetic data of the parent chemical and its metabolites in plasma and brain tissues from separate studies of the three species. Metabolism of primidone and its metabolites varied widely among a sample of three human subjects from two separate studies. Estimated primidone metabolism, as expressed by the maximal velocity Vmax, ranged from 0 to 0.24 mg. min-1.kg-1 for the production of phenobarbital and from 0.003 to 0. 02 mg.min-1.kg-1 for the production of PEMA among three human subjects. Further model simulations indicated that rats were more efficient at producing and clearing phenobarbital and PEMA than mice. However, the overall metabolism profile of primidone and its metabolites in mice indicated that mice were at higher risk of toxicity owing to higher residence of phenobarbital in their tissues and owing to the carcinogenic potential of phenobarbital as illustrated in long-term bioassays. This result was in agreement with a recently finished National Toxicology Program (NTP) carcinogenicity study of primidone in rats and mice.

Standards of laboratory practice: antiepileptic drug monitoring. National Academy of Clinical Biochemistry.

Discussion and development of standards for appropriate monitoring led to the following key recommendations for ordering, sampling, and analyzing antiepileptic drugs: Monitoring should usually be done on trough specimens after steady-state has been reached and always with an appropriate medical indication; non-steady-state concentrations may be indicated in selected situations. Monitoring of free phenytoin and free valproic acid is indicated in specific situations and should be done in serum. The metabolite of primidone, phenobarbital, should be measured concurrently with parent drug, but the active metabolite of carbamazepine does not need to be monitored unless the patient is exhibiting an unusual toxic response that cannot be otherwise explained. Assays used for antiepileptic drug monitoring should display a long-term CV of <10% and preferably <5%. Subtherapeutic and supratherapeutic drug concentrations should be investigated on a regular basis as part of a quality assurance process.

Clinically significant pharmacokinetic drug interactions with carbamazepine. An update.

Carbamazepine is one of the most commonly prescribed antiepileptic drugs and is also used in the treatment of trigeminal neuralgia and psychiatric disorders, particularly bipolar depression. Because of its widespread and long term use, carbamazepine is frequently prescribed in combination with other drugs, leading to the possibility of drug interactions. The most important interactions affecting carbamazepine pharmacokinetics are those resulting in induction or inhibition of its metabolism. Phenytoin, phenobarbital (phenobarbitone) and primidone accelerate the elimination of carbamazepine, probably by stimulating cytochrome P450 (CYP) 3A4, and reduce plasma carbamazepine concentrations to a clinically important extent. Inhibition of carbamazepine metabolism and elevation of plasma carbamazepine to potentially toxic concentrations can be caused by stiripentol, remacemide, acetazolamide, macrolide antibiotics, isoniazid, metronidazole, certain antidepressants, verapamil, diltiazem, cimetidine, danazol and (dextropropoxyphene) propoxyphene. In other cases, toxic symptoms may result from elevated plasma concentrations of the active metabolite carbamazepine-10,11-epoxide, due to the inhibition of epoxide hydrolase by valproic acid (sodium valproate), valpromide, valnoctamide and progabide. Carbamazepine is a potent inducer of CYP3A4 and other oxidative enzyme system in the liver, and it may also increase glucuronyltransferase activity. This results in the acceleration of the metabolism of concurrently prescribed anticonvulsants, particularly valproic acid, clonazepam, ethosuximide, lamotrigine, topiramate, tiagabine and remacemide. The metabolism of many other drugs such as tricyclic antidepressants, antipsychotics, steroid oral contraceptives, glucocorticoids, oral anticoagulants, cyclosporin, theophylline, chemotherapeutic agents and cardiovascular drugs can also be induced, leading to a number of clinically relevant drug interactions. Interactions with carbamazepine can usually be predicted on the basis of the pharmacological properties of the combined drug, particularly with respect to its therapeutic index, site of metabolism and ability to affect specific drug metabolising isoenzymes. Avoidance of unnecessary polypharmacy, selection of alternative agents with lower interaction potential, and careful dosage adjustments based on serum drug concentration monitoring and clinical observation represent the mainstays for the minimisation of risks associated with these interactions.

An interpretation of 14C-urea and 14C-primidone extraction in isolated rabbit lungs.

We measured the venous concentration versus time curves of 14C-urea and 14C-primidone after rapid bolus injections of a vascular reference indicator, fluorescein isothiocyanate dextran, and one of the two 14C-labeled indicators in isolated rabbit lungs perfused with Krebs-Ringer bicarbonate solution containing 4.5% bovine serum albumin at flow rates (F) of 6.67, 3.33, 1.67, and 0.83 ml/sec and with nearly constant microvascular pressure and total lung vascular volume. When we calculated the permeability-surface area product, PS, from the 14C-urea and 14C-primidone outflow curves using the Crone model, the estimates of the PS product were directly proportional to F. However, the fractional change in the PS with flow was different for the two indicators. We also estimated the PS from the same 14C-urea and 14C-primidone data using an alternative model that includes perfusion heterogeneity, estimated in a previous study, and flow-limited and barrier-limited extravascular volumes accessible to both urea and primidone. This model was able to fit the outflow curves of either 14C-urea or 14C-primidone at all four flows studied with one flow-independent PS for each indicator. The ability of the new model to explain the 14C-urea and 14C-primidone data with no flow-dependent change in PS suggests that a change in PS with F estimated using other models such as the Crone model is not sufficient for capillary surface area recruitment.

Clinical pharmacokinetics of antiepileptic drugs in paediatric patients. Part I: Phenobarbital, primidone, valproic acid, ethosuximide and mesuximide.

This article reviews 119 papers published since 1964 on the pharmacokinetics of phenobarbital, primidone, valproic acid, ethosuximide and mesuximide (methsuximide) in paediatric patients. Particular attention has been paid to the role of age in determining the variability of pharmacokinetic parameters, but the effect of other factors, such as different formulations and routes of administration, concomitant treatments, gender and pathological conditions other than epilepsy, have also been considered. Mean phenobarbital terminal half-life (t1/2z) is very long in neonates (45 to 409 hours) and decreases with age. Therefore, a low dose per kilogram (dose/kg) is recommended during the neonatal period. The dose requirement decreases with increasing age, especially in children also taking valproic acid, which inhibits phenobarbital metabolism. Primidone is metabolised to phenobarbital and phenylethylmalonilamide; the metabolic conversion rate is increased by enzyme-inducing drugs and inversely correlated with age, being virtually absent in neonates. Valproic acid is extensively bound to plasma proteins, but there is a high interindividual and intraindividual diurnal variability in the binding, which depends on the concentration of binding proteins (i.e. albumin) and binding modulators (e.g. free fatty acids) but not on age (at least in those patients aged between 3 months and 65 years). The clearance (CL/F) of valproic acid positively correlates with the unbound concentrations and is strongly age-dependent, being low in neonates and high at the end of the first postnatal month, and progressively decreasing from 2 months to 14 years. The combination of these factors leads to a very poor correlation between plasma concentrations and dose/kg (C/D) and between plasma concentrations of total valproic acid and efficacy. Children also taking enzyme-inducing antiepileptic drugs require a larger valproic acid dose/kg, whereas the coadministration of aspirin (acetylsalicylic acid) may decrease the clearance of unbound drug (CLu/F), and thus require a decrease in the daily dose of valproic acid. Ethosuximide is well absorbed, minimally protein bound and slowly eliminated. Lower C/D ratios are reported in children younger than 10 years old than in older children and in individuals also taking enzyme-inducing drugs (i.e. primidone). According to the only available paper on mesuximide in paediatric patients, the C/D ratio is less sensitive to both age and associated therapy.

Practical considerations in anticonvulsant therapy--Part 2.

Epilepsy is, for many patients, a lifelong condition that requires treatment with powerful drugs whose doses must be carefully titrated to avoid both breakthrough seizures and toxicity. The medication regimens used to treat epilepsy are further complicated by the fact that most seizure medications are metabolized in the liver and have the potential for serious pharmacokinetic drug-drug interactions with many other medications. Successful management of epilepsy requires a high degree of cooperation among the patient, the pharmacist, and the treating physician. Such cooperation can ensure that the appropriate treatment and drug preparation are selected, compliance is maintained, and dangerous drug-drug interactions are avoided.

Single-dose kinetics of primidone in human subjects: effect of phenytoin on formation and elimination of active metabolites of primidone, phenobarbital and phenylethylmalonamide.

Effect of repetitive administration of phenytoin (PHT) on the single-dose pharmacokinetics of primidone (PRM) was investigated in 3 healthy male subjects. The peak concentration of unchanged PRM was achieved at 12 and 8 h after the administration of PRM in the absence and the presence of PHT, respectively. The elimination half-life of PRM was decreased from 19.4 +/- 2.2 (mean +/- S.E.) to 10.2 +/- 5.1 h (p < 0.05) and the total body clearance was increased from 24.6 +/- 3.1 to 45.1 +/- 5.1 ml/h/kg (p < 0.01) in the presence of PHT. No significant change was observed for the apparent volume of distribution between the two treatments. In the absence of PHT, the measurable amount (> or = 0.1 mumol/l) of phenobarbital (PB) and phenylethylmalonamide (PEMA) did not appear in the serum until 5.3 and 1.3 h after the PRM administration, and the peak concentrations of PB and PEMA were achieved at 52 and 36 h, but the concentrations of both metabolites were very low (PB 1.3 mumol/l; PEMA 1.7 mumol/l). In the presence of PHT, within 0.8 and 0.5 h after the administration of PRM, the derived PB and PEMA appeared in the serum. About a 6-fold increase in the peak concentrations of both the metabolites were observed (PB 8.2 mumol/l; PEMA 11.0 mumol/l). No significant changes were observed for the elimination half-lives of both PB and PEMA in the absence and presence of PHT.(ABSTRACT TRUNCATED AT 250 WORDS)

Formation of active metabolites of anticonvulsant drugs. A review of their pharmacokinetic and therapeutic significance.

All of the commonly used anticonvulsants drugs, except possibly primidone, are cleared from the human body mainly by metabolism. The metabolites of phenytoin, phenobarbital and ethosuximide have so far not been shown to possess significant pharmacological activity. However, carbamazepine-10,11-epoxide, derived from carbamazepine, has anticonvulsant activity comparable with that of its progenitor, while oxcarbazepine, a new anticonvulsant congener of carbamazepine, is essentially a prodrug for its 10-hydroxy derivative. Valproic acid forms numerous metabolites through a variety of pathways; 2-en valproic acid, a beta-oxidation derivative, probably contributes to its anticonvulsant action, though the extent of the contribution is uncertain. Another metabolite, 4-en-valproic acid, has been considered a possible hepatotoxin and teratogen. N-Methyl-phenobarbital and primidone, though both anticonvulsants in their own right, are metabolised to phenobarbital, which probably mediates much of their antiseizure effect. Primidone also yields the weaker anticonvulsant phenylethylmalonamide. The various benzodiazepine anticonvulsants form numerous metabolites, some of which possess both antiseizure and other forms of pharmacological activity. As yet, there is little understanding of how best to interpret simultaneous plasma concentration measurements of anticonvulsant drug and its active metabolite (or metabolites) in the clinical situation, and the possible roles of anticonvulsant metabolites in the idiosyncratic toxicity of these drugs remain largely unexplored.

The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. I. The influence of administration vehicles.

Although animal models, such as electroshock seizures, pentylenetetrazol (PTZ)-induced seizures and the rotorod test, are widely employed in the search for and evaluation of new anticonvulsant drugs, the important role of diverse technical, biological and pharmacological factors in the interpretation of results obtained with these models is often not recognized. In order to delineate factors other than strain, sex, age, diet, climate, and circadian rhythms, which are generally known, a series of studies was undertaken. In the experiments described here, the influence of administration vehicles and drug formulations on bioavailability, potency and time course of anticonvulsant drugs was studied in mice. Two standard anticonvulsant drugs, primidone and carbamazepine, with poor aqueous solubility were used for these experiments, because water insolubility is a common problem in the laboratory evaluation of anticonvulsant agents. Since vehicles, especially organic solvents or detergents, may exert effects of their own, sensitive electroshock and PTZ seizure threshold tests were used for the assessment of vehicle-related actions. Of various aqueous or lipophilic vehicles tested, only glycofurol increased seizure thresholds, when concentrations exceeding 10% were administered. However, even at a concentration of 30%, the solubilizer did not exert measurable effects in the maximal electroshock seizure (MES) test in mice, but markedly potentiated the effect of primidone. In contrast, polyethylene glycol 400 (PEG 400) up to a concentration of 30% did not affect electrical or chemical seizure thresholds nor did it alter the pharmacological potency of primidone. When primidone or carbamazepine were administered as a suspension in a Tween/water vehicle, their anticonvulsant effects were considerably lower compared to injections of the same doses as a solution.(ABSTRACT TRUNCATED AT 250 WORDS)

The disposition of primidone in elderly patients.

1. The pharmacokinetics and metabolism of primidone at steady-state were studied in 10 elderly patients aged 70-81 years and eight control subjects aged 18-26 years. 2. Primidone half-lives and clearance values (mean +/- s.d.) were similar in the elderly and in the young (12.1 +/- 4.6 vs 14.7 +/- 3.5 h and 34.8 +/- 9.0 vs 33.2 +/- 7.2 ml h-1 kg-1 respectively. 3. The serum concentrations of the metabolites phenylethylmalonamide (PEMA) and phenobarbitone relative to those of parent drug were higher in the elderly than in the young, the difference being significant (P less than 0.01) in the case of PEMA. 4. The renal clearances of primidone, phenobarbitone and PEMA were moderately decreased in the elderly but this reduction was statistically significant only for PEMA. Elderly patients excreted a reduced proportion of unchanged primidone and an increased proportion of PEMA in urine. 5. Ageing is associated with a greater accumulation of PEMA, which is unlikely to have a major clinical significance.

Clearance of phenylethylmalonamide during haemodialysis of a patient with renal failure.

Information is presented for the serum concentrations during haemodialysis of primidone, phenobarbitone, and phenylethylmalonamide (PEMA) in a patient with renal failure receiving chronic primidone therapy. The concentrations of drug and metabolites fell during haemodialysis, but PEMA concentrations were above normal at all times. The average renal clearance of PEMA during 6 h of dialysis was found to be 84.7 +/- 4.6 ml min-1.

Comparison of the anticonvulsant efficacy of primidone and phenobarbital during chronic treatment of amygdala-kindled rats.

In amygdala-kindled rats, single-dose administration of primidone did not reduced seizure activity 2 h after i.p. injection, i.e. when plasma levels of the drug were highest, but significant anticonvulsant effects were found 24 h after administration, when the drug was almost completely eliminated. During chronic treatment with primidone, marked anticonvulsant efficacy was determined after 3-15 days of three times daily treatment with 50 mg/kg i.p., indicating that this effect was due to the accumulation of metabolites, especially phenobarbital. Maximum anticonvulsant activity attained during chronic primidone medication was almost equal to that found during chronic treatment of kindled rats with phenobarbital, 30 mg/kg once daily. However, drug plasma level determinations during both treatments showed that on days when both treatments were about equieffective, levels of metabolically derived phenobarbital in the primidone group were significantly lower than levels in rats treated with phenobarbital alone, thus indicating that primidone potentiated the anticonvulsant effect of metabolically derived phenobarbital. Additional evidence for potentiation of the anticonvulsant effect of phenobarbital by primidone was found in single dose experiments with combined injection of both drugs, whereas side-effects, such as ataxia and muscle relaxation, induced by phenobarbital were not increased by combined treatment with primidone. Accordingly, side-effects occurring during chronic primidone treatment were less pronounced than side-effects found during chronic phenobarbital medication. In both treatment groups, tolerance to the anticonvulsant effect developed during the 2nd week of administration, while attenuation of side-effects took place already in the first week. Following cessation of treatment, signs of physical dependence, such as withdrawal hyperexcitability and weight loss, were observed. The data indicate that, at least in kindled rats, the anticonvulsant activity of primidone during chronic treatment is due to the combined and possibly synergistic actions of primidone and metabolically derived phenobarbital.