Human health risk assessment of pharmaceuticals in water: an uncertainty analysis for meprobamate, carbamazepine, and phenytoin.

This study presents a step-wise development of a quantitative pharmaceutical risk assessment (QPhRA, hereafter) framework, including Monte Carlo uncertainty analysis for meprobamate, carbamazepine, and phenytoin during (1) accidental exposures of stream water and fish consumption and (2) direct ingestion of finished drinking water for children and adults. Average hazard quotients of these pharmaceuticals (i.e., the ratio of values of chronic daily intake to acceptable daily intake) were found to lie between 1x10(-10) and 3x10(-5) and 99 th percentile values of hazard quotients were found to be less than 1x10(-4) for both sub-populations, indicating no potential risks of adverse effects due to pharmaceuticals exposures. In addition, pharmaceutical concentrations were also observed to be lower than their respective calculated acceptable daily intake-equivalent drinking water levels, indicating no potential human health risks. To the authors' knowledge, for the first time in QPhRA studies, this study has attempted to characterize and quantify effects of factors, such as considerations for sensitive sub-populations using subpopulation-specific toxic endpoints and use of pharmaceutical concentrations in stream and finished drinking waters on risk estimates. Acceptable daily intake was observed to be the primary contributor (>93% variance contribution) in the overall uncertainties of estimates of hazard quotients, followed by fish consumptions and pharmaceutical concentrations in water. Further research efforts are required to standardize use of acceptable daily intake values to reduce large variability in estimation of hazard quotients.

Carisoprodol pharmacokinetics and distribution in the nucleus accumbens correlates with behavioral effects in rats independent from its metabolism to meprobamate.

Carisoprodol (Soma®) is a centrally-acting skeletal-muscle relaxant frequently prescribed for treatment of acute musculoskeletal conditions. Carisoprodol's mechanism of action is unclear and is often ascribed to that of its active metabolite, meprobamate. The purpose of this study was to ascertain whether carisoprodol directly produces behavioral effects, or whether metabolism to meprobamate via cytochrome P450 (CYP450) enzymatic reaction is necessary. Rats were trained to discriminate carisoprodol (100 mg/kg) to assess time course and whether a CYP450 inhibitor (cimetidine) administered for 4 days would alter the discriminative effects of carisoprodol. Additionally, pharmacokinetics of carisoprodol and meprobamate with and without co-administration of cimetidine were assessed via in vivo microdialysis combined with liquid-chromatography-tandem mass spectrometry from blood and nucleus accumbens (NAc). The time course of the discriminative-stimulus effects of carisoprodol closely matched the time course of the levels of carisoprodol in blood and NAc, but did not match the time course of meprobamate. Administration of cimetidine increased levels of carisoprodol and decreased levels of meprobamate consistent with its interfering with metabolism of carisoprodol to meprobamate. However, cimetidine failed to alter the discriminative-stimulus effects of carisoprodol. Carisoprodol penetrated into brain tissue and directly produced behavioral effects without being metabolized to meprobamate. These findings indicate that understanding the mechanism of action of carisoprodol independently of meprobamate will be necessary to determine the validity of its clinical uses.

High-dose carisoprodol during pregnancy and lactation.

OBJECTIVE: To report a case of use of high-dose carisoprodol during pregnancy and breast-feeding. CASE SUMMARY: A 28-year-old woman with severe back muscle spasm took carisoprodol 2800 mg/day before and throughout an uncomplicated pregnancy and while exclusively breast-feeding her infant during the first month after birth. Serum drug concentrations of carisoprodol and the active metabolite meprobamate were measured in the mother and infant. Concentrations of these agents also were measured in breast milk. Developmental toxicity was not observed in the near-term infant, whose birth weight was at the 10th percentile for gestational age. Only slight sedation was noted in the infant during breast-feeding, and no signs or symptoms of withdrawal were noted when nursing was stopped. DISCUSSION: Carisoprodol and meprobamate are excreted into breast milk. Although the published human pregnancy data are limited to 15 cases, carisoprodol does not appear to cause developmental toxicity (growth restriction, structural anomalies, functional/neurobehavioral deficits, or death), even when the mother is taking high doses. No signs or symptoms of withdrawal were noted in our infant or in a previously published case when breast-feeding was stopped. Long-term follow-up has not been conducted in exposed infants, and the possibility of functional/neurobehavioral l deficits appearing later in life cannot be excluded. CONCLUSIONS: Except for mild sedation, no other toxicity was observed in a near-term infant exposed to carisoprodol throughout gestation and during breast-feeding in the first month after birth.

Pharmacokinetic modeling of carisoprodol and meprobamate disposition in adults.

Carisoprodol is a widely prescribed muscle relaxant and is also a drug known to be a subject to abuse. Despite the fact that carisoprodol has been available for prescription since 1959, a number of gaps in our knowledge of the toxicokinetics of this common drug exist. For example, the volume of distribution (Vd) for carisoprodol in humans has not been reported. A two-compartment pharmacokinetic model describing carisoprodol metabolism and that of the primary metabolite, meprobamate, was developed to better understand the pharmacokinetics of this drug. The model accounts for first pass metabolism of carisoprodol and was able to replicate the data from several previously reported data sets. Based on an analysis of four different data sets, the Vd for carisoprodol ranged from 0.93 to 1.3 L/kg, while that for meprobamate ranged from 1.4 to 1.6 L/kg. The model was also used to estimate the probable dose of this drug in an individual where questions concerning the drug's role in her death had been posed. The model may, therefore, have significant utility for estimating doses of carisoprodol in medicolegal cases.

Formation of meprobamate from carisoprodol is catalysed by CYP2C19.

Carisoprodol is a muscle relaxant analgesic, which has an active metabolite i.e. meprobamate. We conducted an open three-panel single-dose administration study with 15 healthy volunteers: five poor metabolizers of mephenytoin, five poor metabolizers of debrisoquine and five extensive metabolizers of both substrates. The aim was to investigate if the elimination of carisoprodol and meprobamate is dependent on the two metabolic polymorphisms of mephenytoin and debrisoquine. The subjects were given single oral doses of 700 mg carisoprodol and 400 mg meprobamate on separate occasions. The disposition of carisoprodol was clearly correlated to the mephenytoin hydroxylation phenotype. The mean serum clearance of carisoprodol was four times lower in poor metabolizers of mephenytoin than in extensive metabolizers, which confirms the hypothesis from our previous study that N-dealkylation of carisoprodol cosegregates with the mephenytoin hydroxylation polymorphism. However, mean serum clearance of meprobamate did not differ between the two groups. Also, polymorphic debrisoquine hydroxylation did not influence the elimination of carisoprodol or meprobamate. Poor metabolizers of mephenytoin thus have a lower capacity to metabolize carisoprodol and may therefore have an increased risk of developing concentration dependent side-effects such as drowsiness and hypotension, if treated with ordinary doses of carisoprodol.

[The effect of phytin, benzonal and their combination administered prophylactically on the pharmacodynamics of drugs metabolized in the liver in hypokinesia]. / Vliianie fitina, benzonala i ikh kombinatsii pri profilakticheskom vvedenii na farmakodinamiku lekarstvennykh veshchestv, metaboliziruiushchikhsia v pecheni pri gipokinezii.

Hexenal, meprobamate, amidopyrine and ethylmorphine produced a significantly marked effect in animals under hypokinesia as compared with normal rats. When phytin, benzonal and their combination were used for preventive purposes, impaired pharmacodynamics of the tested drugs metabolizing in the liver disappeared. The investigations demonstrated that the preventive use of phytin in combination with benzonal is the most optimal in correcting the impairments of drug pharmacodynamics in hypokinesia.

Factors affecting carisoprodol metabolism in pain patients using urinary excretion data.

Carisoprodol is a skeletal muscle relaxant prescribed to treat pain. Carisoprodol is metabolized to meprobamate, an active metabolite with anxiolytic effects, by the genetically polymorphic CYP2C19 enzyme. Concomitant use of CYP2C19 substrates or inhibitors may alter carisoprodol metabolism, with therapeutic and/or toxic implications for effectively treating patients with pain. This was a retrospective analysis of urinary excretion data collected from patients with pain from March 2008 to May 2011. Carisoprodol and meprobamate urine concentrations were measured by liquid chromatography-tandem mass spectrometry, and the metabolic ratio (MR) of meprobamate to carisoprodol concentrations was determined in 14,965 subjects. The MR geometric mean and 95% confidence interval (95% CI) of the young group (105, 95% CI = 99.1-113) were ∼47.4% higher than the middle-aged group (71.9, 95% CI = 70-73.8) and nearly two times higher than the elderly group (54.4, 95% CI = 51.3-57.6). Females had a 20.7% higher MR compared with males. No significant change in the MR was observed with overall CYP2C19 inhibitor or substrate use. However, evaluation of individual inhibitors showed co-administration with esomeprazole or fluoxetine was associated with a 31.8 and 24.6% reduction in MR, respectively, compared with controls (P < 0.05). Omeprazole did not significantly affect the MR. Patient-specific factors such as age, sex and co-medications may be important considerations for effective carisoprodol therapy.

Pharmacokinetics of meprobamate in overdose treated with continuous venovenous hemodiafiltration (CVVHDF).

We report a case of massive suicidal overdose of meprobamate leading to cardiovascular collapse, respiratory failure, and severe central nervous system depression. We observed first-order elimination kinetics despite significant overdose, and demonstrated effectiveness of continuous venovenous hemodiafiltration (CVVHDF) for extracorporeal removal of meprobamate in this patient. Total body clearance was calculated to be 87 mL/minute, with 64 mL/minute (74%) due to CVVHDF. CVVHDF was stopped after 36 hours, and the patient made an uneventful recovery.

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.

Postmortem carisoprodol and meprobamate concentrations in blood and liver: lack of significant redistribution.

Carisoprodol is a therapeutic and occasionally abused centrally acting muscle relaxant. We compare central blood and liver concentrations of carisoprodol and the metabolite meprobamate to concentrations in peripheral blood in 11 medical examiner cases. Specimens were initially screened for alcohol and simple volatiles by gas chromatography (GC)-flame ionization detection headspace analysis, enzyme-linked immunosorbent array for drugs of abuse, and therapeutic drugs by GC-mass spectrometry (MS). Carisoprodol, when detected by the therapeutic drug screen, was confirmed and quantified by a specific GC-MS procedure. The results suggest that when ingested with other medications, carisoprodol may be a contributing factor in death, even when present at therapeutic concentrations. Considering the cases studied, together with previously published therapeutic and fatal concentrations, blood carisoprodol concentrations greater than 15 mg/L and liver concentrations greater than 50 mg/kg may be considered excessive and potentially fatal. Carisoprodol central blood to peripheral blood ratios averaged 1.31 + 0.33 (mean ± standard deviation), and liver to peripheral blood, 2.83 ± 1.51. Meprobamate central blood to peripheral blood ratios averaged 0.92 ± 0.22, and liver to peripheral blood, 1.25 ± 0.69. The low liver to peripheral blood ratio (less than 5), taken together with the low central blood to peripheral blood ratio, is an indicator that both carisoprodol and meprobamate lack the potential to exhibit postmortem redistribution.

Meprobamate kinetics during and after terminated hemoperfusion in acute intoxications.

We report four cases of severe meprobamate intoxication. Maximal plasma levels reached 800 (176), 816 (180), 863 (190) and 923 mumol/l (203 mg/l). All patients survived without sequelae including one patient resuscitated from cardiac arrest. The clinical course was complicated by coma, hypotension, and hypothermia in all patients. Three cases were treated with charcoal hemoperfusion with mean hemoperfusion clearance ranging from 134-164 ml/min compared to 174 ml/min in one case treated with resin filter and the same blood flow of 200 ml/min. In two cases, a mean renal meprobamate clearance of 15 and 23 ml/min was calculated comprising only 9-15% of the hemoperfusion clearance. The amount of meprobamate removed by hemoperfusion ranged from 1.6-6.2 g. In one case, the half-life of plasma meprobamate during hemoperfusion was 2.6 hours compared to 8.3 hours after hemoperfusion. Thus the half-life was reduced more than 3-fold. These data show that hemoperfusion may be indicated in severe meprobamate intoxication.

Continuous arteriovenous hemoperfusion in meprobamate poisoning.

A patient with severe meprobamate poisoning presented within 4 h after suicidal ingestion of an unknown amount of the drug. The patient was unconscious, unresponsive, and hypotensive. Continuous arteriovenous hemoperfusion with coated activated charcoal resulted in a clearance of 198.8 +/- 15.6 mL/min with an extraction ratio of 0.66 +/- 0.05 (n = 3). There was almost complete elimination of the drug from the blood by 16 h. Continuous arteriovenous hemoperfusion, which can be performed in areas where dialysis facilities are not available, may be an effective adjunct to the treatment of acute meprobamate intoxication, particularly in patients with profound hypotension.

Experimental studies on effects of long-term ethanol administration on meprobamate elimination from blood.

When rabbits were administered different amounts of ethanol during 25 and 50 days, the elimination of meprobamate from blood was not accelerated at daily ethanol dose of 0.4g/kg. The elimination was accelerated a little at daily ethanol dose of 0.8g/kg and markedly accelerated at the dose of 1.6g/kg. However, it was not accelerated furthermore at the dose of 2.4g/kg. Thus, accelerative effect of long-term ethanol administration on meprobamate metabolism may be greatly related to ethanol dosage and it is considered that the accelerative effects reach maximum at blood ethanol concentrations more than 1mg/ml. Also, elimination of meprobamate from brain in rats was fairly accelerated by long-term ethanol administration at the daily dose of 0.4g.

Transfer of carisoprodol to breast milk.

There is no published information on the transfer of the centrally acting muscle relaxant carisoprodol and its active metabolite meprobamate into breast milk. The objective of this study was to quantify the excretion of carisoprodol and meprobamate in human milk and estimate the dose received by breast-fed infants. The concentrations of carisoprodol and meprobamate were measured in breast milk on 4 consecutive days at steady-state conditions in one woman using carisoprodol 2100 mg/d. The average milk concentrations were 0.9 microg/mL for carisoprodol and 11.6 microg/mL for meprobamate. Based on the milk concentrations measured, the absolute dose ingested by an exclusively breast-fed infant could be estimated at 1.9 mg/kg per day, and the relative dose would be 4.1% of the weight-adjusted maternal dose. No adverse effects were observed in the infant, but the infant was partly fed with formula because of insufficient maternal milk production. Thus, the authors consider that at least during prolonged use, lactation is generally inadvisable until more clinical data are available.

Pharmacological studies on meprobamate incorporation in human beard hair.

The time course of appearance of meprobamate in beard hair after single oral administration (400, 800, or 1200 mg) was monitored in 3 groups of 4 subjects by GC/MS. Meprobamate appeared in beard hair approximately 4-5 days after administration and peaked during the 7-9th day. Drug levels in beard hair appeared to be dose-related.

Interactive effects of acute ethanol administration on meprobamate levels in blood and brain of rabbit and rat.

In the simultaneous administration of meprobamate and ethanol to rabbits, the blood meprobamate concentration (BMC) increased greatly when the maximum blood ethanol concentration (BECmax) exceeded 1.0 mg/ml. Thus, we subjected the rabbits to continuous infusion of ethanol so as to make the blood ethanol concentration (BEC) constant and administered meprobamate by intravenous injection. Elimination of meprobamate became slow at about the BEC of 0.5 mg/ml and the degree reached almost maximum around the BEC of 1.0 mg/ml. The elimination rate did not change any more even when the BEC was raised higher. In the study conducted to elucidate the relationship between the BMC and brain meprobamate concentration (BrMC) using rats, it was found that meprobamate would show similar movements and its level would rise extremely by an acute administration of ethanol. It was indicated that the effect of ethanol on reinforcement of meprobamate activity would appear strongly by potentiation effect.

Biological valuation of extra-corporeal techniques in acute poisoning.

The efficiency of dialysis methods a/o hemoperfusion in acute poisoning cannot be clinically estimated, because: a) Concomitant intestinal absorption, hepatic metabolism and urinary excretion must be taken into account. b) With supportive treatment alone, spontaneous recovery usually occurs in 98% of the intoxications in Intensive Care Units. The efficiency of these methods can only be estimated biologically. Measuring the blood level at the beginning and the end of the treatment as well as measuring the clearances of the drug is misleading. A better method is to measure the amount of extracted drug, either indirectly by calculation (from hourly differences of arteriovenous measures of drug concentration multiplied by the blood flow) or directly by elution of the cartridge or measures in dialysis fluid. Plasma kinetics under dialysis a/o hemoperfusion should be compared with spontaneous toxicokinetic of the substance and not with pharmacokinetic data. The experience of toxicologists has shown dialysis a/o hemoperfusion to be ineffective for drugs with weak extra-cellular distribution (such as Digoxine, Tricyclic drugs, heavy Metals, Colchicine). In the case of intoxication with Paraquat or Paracetamol, there is a negative correlation between the amount of removed intoxicant and the survival: death is likely to occur when the procedure has been very productive. In the case of intoxication by hypnotic drugs, one hemodialysis a/o hemoperfusion allows the removal of an average of 4-12% of the ingested barbiturates, 7-17% of the ingested Meprobamate. Whether these results can be judged satisfactory, life-saving of insignificant is largely a matter of personal standards.

Effect of long-term ethanol administration on meprobamate level in brain of rat.

Effect of long-term ethanol administration on brain meprobamate concentration (BrMC) was investigated using rats. In ethanol-non-pretreated rats, the average ratio of the maximum BrMC (BrMCmax) to the maximum blood meprobamate concentration (BMCmax) was 0.75 when 25 mg/kg meprobamate were intraperitoneally administered to rats singly or together with ethanol (2 g/kg or 4 g/kg). By a pretreatment of the animals with ethanol at the daily dose of 0.4 g or 0.6 g for 25 days, the average ratio of BrMCmax to BMCmax was 0.91 when the same dose of meprobamate were given into the abdominal cavity. It was considered that by long-term ethanol administration the permeability of blood-brain barrier to meprobamate might be accelerated, resulting in an increase in BrMC.

[Characteristics of drug pharmacodynamics in irradiated rats]. / Osobennosti farmakodinamiki lekarstvennykh veshchestv u obluchennykh krys.

A whole-body exposure of rats to 8 Gy radiation is ineffective in 3 days, and in 6 days, it prolongs considerably the effect and increases the pharmacological activity of hexenal, meprobamate, ethylmorphine, and amidopyrine, inhibits the activity of amidopyrine demethylase, aniline hydroxylase, NADPH-cytochrome c reductase, and reduces the content of protein, cytochromes P-450 and b5 in a microsomal liver fraction.