Efficacy and safety of oral iron chelating agent deferiprone in beta-thalassemia and hemoglobin E-beta thalassemia

OBJECTIVES: To assess efficacy and safety of oral iron chelating agent deferiprone (DFP) in patients with beta thalassemia and hemoglobin E-beta thalassemia. DESIGN: Non-randomized study. SETTING: Hematology Out-Patient Department. SUBJECTS: Forty-one patients of beta thalassemia and hemoglobin E-beta thalassemia. INTERVENTIONS: DFP was given to 20 patients, 10 patients of beta thalassemia and 10 with hemoglobin E-beta thalassemia; the rest were taken as controls. RESULTS: A significant fall in serum ferritin was observed in the study group along with rise in urinary iron excretion (p < 0.05). Adverse effects of DFP were nausea and vomiting (30%), significant arthropathy requiring stopping of the drug (30%), and reversible neutropenia in one patient. All these complications could be managed easily with medical supervision and no death or permanent disability was seen. CONCLUSIONS: DFP is an effective and fairly well tolerated oral iron chelating agent. The side effects that occur can be tackled easily if monitored properly.     

Iron-balance and dose-response studies of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in iron-loaded patients with sickle cell disease

Several life-threatening complications of the common disorder sickle cell disease require management with red blood cell transfusions and, hence, long-term iron-chelating therapy. The efficacy of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) has not previously been determined in patients with sickle cell disease. We compared the efficacy of L1 to that of standard-dose subcutaneous deferoxamine in four regularly transfused patients with homozygous sickle cell disease, who had evidence of severe iron overload and a history of poor compliance with deferoxamine. Determination of 24-hour urinary iron excretion conducted over 5 days immediately after transfusion showed that the mean daily urinary iron excretion induced by L1 at 75 mg/kg/d (0.48 +/- 0.23 mg/kg) was equivalent to that induced by deferoxamine at 50 mg/kg/d (0.39 +/- 0.06 mg/kg). In two of three patients studied, a significant (P < .025) increase in mean daily urinary iron excretion was achieved when the dose of L1 was increased to 100 mg/kg/d. Total iron balance studies, which quantitated both urinary and stool iron excretion on L1 and deferoxamine, determined that mean total daily iron excretion induced by deferoxamine (0.88 +/- 0.05 mg/kg) was significantly greater (P < .05) than that induced by L1 (0.53 +/- 0.17 mg/kg), attributable to the significantly greater stool iron excretion during deferoxamine treatment (0.50 +/- 0.16 mg/kg/d) compared with that measured during L1 treatment (0.12 +/- 0.08 mg/kg/d, P < .01). Stool iron excretion accounted for a significantly greater percentage of total iron excretion during deferoxamine treatment (59% +/- 20%) than during L1 treatment (23% +/- 14%, P < .01). These iron balance studies are the first to compare total iron excretion induced by L1 with that achieved by deferoxamine. They demonstrate that the mean total daily iron excretion during L1 treatment (0.53 +/- 0.17 mg/kg) is sufficient to maintain net negative iron balance in most regularly transfused patients with sickle cell disease. Because long-term compliance with L1 has been shown previously to be superior to that with deferoxamine in patients with homozygous beta-thalassemia, the use of L1 should increase the long-term effectiveness of iron chelation in patients with sickle cell disease.     

Population pharmacokinetics and pharmacodynamics of oral levodopa in parkinsonian patients

Unlike most secretory cells, high extra cellular calcium inhibits rather than stimulates hormonal secretion in several cells such as parathyroid cells, Juxtaglomerular cells and osteoclast. To gain further insight into the common but unique stimulus-secretion coupling mechanism in these cells, bovine parathyroid slices were incubated in various conditions of Krebs-Ringer (KR) solution containing essential amino acids. Parathyroid cells showed the inverse dependency of secretion on extra cellular calcium concentration as we expected. Ammonium acetate overcame the inhibitory effect of 2.5 mM of calcium and the maximum effect was as much as the five times of the basal value, while there was a little additive effect under 0 mM CaCl2. PTH secretion was biphasic according to the change of extra cellular osmolarity and the lowest response was observed at 300 mOsm/l. In Na-rich KR solution, high concentration of nigericin (> 10(-4)M) completely overcame the inhibitory effect of 2.5 mM CaCl2 and the maximum stimulatory effect was 8 times greater whereas it was only 2 times greater without CaCl2. In K-rich KR solution that abolished the K-gradient between the extra cellular solution and the cytoplasm, the rate of PTH secretion increased, and furthermore the addition of nigericin increased the rate of secretion significantly. The results above suggested that the osmotic swelling of the secretory vesicle in parathyroid cells might promote exocytosis as in Juxtaglomerular cells. We propose that the swelling of the vesicle is also prerequisite for secretion in several cells inhibited paradoxically by Ca++, whatever the signal transduction pathway for swelling of the secretory granules induced by the lowering of Ca++ in cytoplasm are.     

The effect of intravenous and oral fluconazole on the pharmacokinetics and pharmacodynamics of intravenous alfentanil

The growth-promoting activity of PDGF-BB was studied on the adult osteoclasts in the present study. The PDGF receptor beta was detected on the osteoclast membrane through immunohistochemistry (LSAB method) and immunomicroscopy. The PDGF-BB was exerted on the osteoclasts that adhered to the bone slice at concentrations of 0, 10, 20, 30, and 40 ng/ml. The volume of Howship's lacuna augmented significantly and the number of resorption pits also increased with its dose (p < 0.01). The activity of both total acid phosphatase (ACP) and tartrate-resistant acid phosphatase (TRAP) increased significantly. These results suggest that PDGF-BB promotes adult osteoclastic bone resorption directly through PDGF receptor beta and is believed to play important roles in the bone healing process and reconstruction.     

Caco-2 cell permeability of a new (hydroxybenzyl)ethylenediamine oral iron chelator: correlation with physicochemical properties and oral activity

This study describes the transport of CGP 75254A, a novel oral iron chelator, across Caco-2 cells in an attempt to model intestinal epithelial cell permeability in man. CGP 75254A was dosed to the apical side of Caco-2 cell monolayers, together with [14C]mannitol as an internal permeability standard. The apparent permeability (Papp) was calculated from the cumulative appearance of drug in the basolateral fluid with time. The [14C]mannitol Papp indicated that the Caco-2 monolayers remained intact and that the iron chelator was not toxic to the cells. Permeabilities of CGP 75254A were compared with the Caco-2 permeabilities of compounds of known absorption in man. The results predict that absorption of CGP 75254A is likely to be virtually complete at pH values between 5.5 and 7.0. However, at pH 8.0 permeability is predicted as negligible. Cell permeability data are in full accordance with key physicochemical properties of CGP 75254A and suggest that the drug is passively absorbed. The results, which suggest likely quantitative absorption in vivo, are supported by preliminary pharmacological experiments in marmosets.     

The use of microdialysis in pharmacokinetics and pharmacodynamics

Microdialysis is a new in vivo sampling technology applied to the study of pharmacokinetics and drug metabolism in the blood and soft tissues of living systems. A small-diameter probe containing a dialysis membrane is implanted into tissue and perfused with a suitable fluid. Low-molecular-weight substances passively diffuse through the semipermeable membrane along a concentration gradient, resulting in the collection of purified dialysate samples. The advantage of this approach over blood sampling and dissection of tissues is the ability to sample blood and extracellular fluid with minimal tissue damage or alteration of fluid balance. Sampling several tissues simultaneously and continuously in animal models allows data to be obtained that more directly reflect interactions of drugs at their sites of activity and detoxification. Techniques such as this will have a tremendous impact on preclinical and clinical pharmacologic research.     

The pharmacokinetics and steady state pharmacodynamics of mivacurium in children

BACKGROUND: The main causes of allograft failure after cardiac transplantation are primary graft dysfunction, intractable acute rejection, and coronary graft disease. Despite the important progress in the last several years in graft preservation, surgical techniques, immunosuppression, and treatment of coronary graft disease, retransplantation in selected cases is the only way to achieve long-term recipient survival. METHODS: We compare here in a case-control study 24 retransplantations with 47 first transplants in patients matched for date of transplantation. RESULTS: Between 1973 and 1996, 1,063 patients underwent cardiac transplantation in our institution. In this cohort, 22 patients had a total of 24 retransplantations (2 second-time retransplantations). The causes of retransplantations were primary graft failure (n=4), acute rejection (n=7), coronary graft disease (n=11), and miscellaneous (n=2). Survival at 1 and 5 years of patients with retransplantations is 45.5% and 31.2%, and survival of control patients is 59.4% and 38.8% (p=0.07). An interval between first transplantation and retransplantation shorter (n=11) or longer (n=13) than 1 year is associated with a 1-year survival of 27.3% and 61.5% and a 4-year survival of 27.3% and 46%, respectively (not significant). Intervals shorter than 1 year between first transplantation and retransplantation were exclusively secondary to primary graft failure or intractable acute rejection. CONCLUSIONS: In the face of lack of donor grafts, these and other data indicate that retransplantation should be considered cautiously, especially when the interval between the first transplantation and retransplantation is short.     

The effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of buspirone

OBJECTIVE: The effects of fluvoxamine, a selective serotonin (5-HT) reuptake inhibitor antidepressant, on the pharmacokinetics and pharmacodynamics of buspirone, a non-benzodiazepine anxiolytic agent, were investigated. METHODS: In a randomized, placebo-controlled, two-phase cross-over study, ten healthy volunteers took either 100 mg fluvoxamine or matched placebo orally once daily for 5 days. On day 6, 10 mg buspirone was taken orally. Plasma concentrations of buspirone and its active metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP), were measured up to 18 h and the pharmacodynamic effects of buspirone up to 8 h. RESULTS: The total area under the plasma buspirone concentration-time curve was increased 2.4-fold (P < 0.05) and the peak plasma buspirone concentration 2.0-fold (P < 0.05) by fluvoxamine, compared with placebo. The half-life of buspirone was not affected. The ratio of the total area under the plasma concentration-time curve of 1-PP to that of buspirone was decreased from 7.4 [6.3 (SD)] to 4.4 (3.6) by fluvoxamine (P < 0.05). The results of the six pharmacodynamic tests remained unchanged. CONCLUSION: Fluvoxamine moderately increased plasma buspirone concentrations and decreased the production of the active 1-PP metabolite of buspirone. The mechanism of this interaction is probably inhibition of the CYP3A4-mediated first-pass metabolism of buspirone by fluvoxamine. However, this pharmacokinetic interaction was not associated with impairment of psychomotor performance and it is probably of limited clinical significance.     

The effects of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam

We studied the interaction of azole antimycotics with intravenous (IV) and oral midazolam using a cross-over design in 12 volunteers, who ingested placebo, itraconazole, or fluconazole for 6 days. A 7.5-mg dose of midazolam was ingested on the first day, 0.05 mg/kg was administered IV on the fourth day, and 7.5 mg orally on the sixth day. Itraconazole reduced the clearance of IV midazolam by 69% and fluconazole reduced the clearance of IV midazolam by 51% (P < 0.001). A single dose of itraconazole and fluconazole increased the area under the oral midazolam concentration-time curve [AUC(0-infinity)] 3.5-fold (P < 0.001) and the peak concentration two-fold (P < 0.05) compared to placebo. On the sixth day the AUC(0-infinity) of oral midazolam was almost seven times greater with itraconazole (P < 0.001) and 3.6 times greater with fluconazole (P < 0.001) than without the antimycotics. The psychomotor effects of midazolam were also profoundly increased (P < 0.001). The psychomotor tests demonstrated only a weak interaction between the antimycotics and IV midazolam. When bolus doses of midazolam are given for short- time sedation, the effect of midazolam is not increased to a clinically significant degree by itraconazole and fluconazole, and it can be used in normal doses. However, the use of large doses of IV midazolam increases the risk of clinically significant interactions also after IV midazolam. Use of oral midazolam with itraconazole and fluconazole should be avoided.     

Nitrosourea pharmacodynamics in relation to the central nervous system

Time-response curves were established for the effect of 3 doses of pimozide, a potent and specific dopamine receptor blocker, on deprivation-induced drinking in rats. Injections occurred once every 3 days at intervals of 2, 4, 8, and 16 hr prior to the daily 15 min drinking period. Pimozide produced a significant attenuation in the amount of water normally consumed (on nondrug days) whose degree varied with the proximity of the injection to the drinking period. Only the 2 higher doses (0.5 and 1.0 mg/kg) produced a significant dose dependent effect which was strongest at the 2 hr interval and which gradually weakened by the 8th post injection hr. The relevance of these findings for a direct versus an indirect action of the drug on water intake is discussed.     

Comparison of the metabolism of 2 injectable iron preparations (sorbitol iron and polymaltose iron) with the metabolism of transferrin and hemoglobin iron

Iron distribution in the different organs and chemical compartments of the rat has been studied after intravenous injection of 59Fe-sorbitol (Jectofer-Astra) and 59Fe-polymaltose (Fer Hausmann Lucien) and compared with the metabolism of 59Fe bound to transferrin and to hemoglobin. Both parenteral iron preparations are utilized more slowly than Iron-transferrin. The speed of red cell incorporation of 59Fe from sorbitol is similar to the hemoglobin iron utilization (half incorporation in red cells: 4 to 5 days). Iron polymaltose is much more slowly utilized (half incorporation in the red cells: 13 to 15 days). One third of the 59Fe from sorbitol is eliminated in urine, the remaining iron being taken up to 60% by the liver and to 30% by the bone marrow. It is very quickly catabolized, since as early as the first hour after injection most of the 59Fe is bound to polymaltose till the 14th day. Between the third and fourth week 25% of the 59Fe from polymaltose is found in hemosiderin. These metabolic differences are also found in man: 59Fe from iron sorbitol is found in urine after injection, is mobilized by desferrioxamine after six days, and eliminated through dialysis membranes. On the other hand the 59Fe from polymaltose is slowly but completely utilized and not mobilized by desferrioxamine in the first week after injection. The data give the indications for use and the pharmacokinetics of two forms of parenteral iron and oral preparations in the treatment of iron deficiency.     

The effect of the antimycotic itraconazole on the pharmacokinetics and pharmacodynamics of diazepam

The azole antimycotic itraconazole is a potent and relatively unspecific inhibitor of cytochrome P450 enzymes and has a potentially dangerous interaction with midazolam and triazolam. The possible interaction between itraconazole and diazepam was investigated in a double-blind, randomized, cross-over study. Ten healthy volunteers were given orally placebo or itraconazole 200 mg a day for 4 days. The challenge dose of 5 mg of diazepam was ingested on the fourth day, after which plasma samples were collected and psychomotor performance tests were carried out for 42 h. Despite a statistically significant small increase in the area under the plasma diazepam concentration-time curve and the elimination half-life of diazepam, there was no clinically significant interaction as determined by the psychomotor performance tests. The lack of significant first-pass metabolism and the different metabolic pathways of diazepam explain the smaller interaction potential of diazepam compared with midazolam and triazolam. Diazepam, unlike midazolam and triazolam, can be prescribed in usual doses for patients receiving itraconazole and probably other inhibitors of P4503A4, at least when diazepam is used as single doses.     

The pharmacodynamics and pharmacokinetics of the 5HT1B/1D-agonist zolmitriptan in healthy young and elderly men and women

OBJECTIVE: Zolmitriptan is a selective 5HT1B/1D-agonist for the treatment of migraine. In this study we investigated the cardiovascular and central nervous system effects and the pharmacokinetics of zolmitriptan in young and elderly adults. METHODS: Twelve young adult and 12 elderly volunteers received single doses of 5, 10, and 15 mg zolmitriptan during a randomized, double-blind, placebo-controlled study. Blood pressure, heart rate, ECG, and central nervous system effects were monitored, and pharmacokinetic parameters of zolmitriptan and its metabolites calculated. RESULTS: Zolmitriptan did not affect heart rate and had little effect on systolic blood pressure in the young adults. In the elderly, mean peak supine systolic blood pressure values were 9 to 16 mm Hg higher after zolmitriptan than after placebo. Mean peak diastolic pressure was 6 to 10 mm Hg higher in both age groups. These changes were transient. Postural changes in blood pressure were unaffected. There was a dose-related increase in sedation, but the magnitude of the effects was small. Mean observed peak plasma concentration (Cmax) and area under the plasma concentration-time profile [AUC(0-infinity)] for zolmitriptan and its active N-desmethyl metabolite were similar in both age groups but higher in young women than in young men. Metabolite/parent ratios probably the result of greater first-pass metabolism in young men. Zolmitriptan half-life was 2.8 to 3.6 hours in the elderly compared with 2.7 to 2.9 hours in young adults. Mean Cmax and AUC(0-infinity) for the inactive, N-oxide, and the indole acetic acid metabolites were higher in the elderly, associated with lower renal clearance. CONCLUSIONS: Zolmitriptan was well tolerated, with an effect of age on its effects on blood pressure and the pharmacokinetics of its metabolites. The data suggest no need for dose adjustment for age. In young subjects, concentrations were higher in women than in men, but the differences were insufficient to justify dosage adjustment.     

Circadian changes in the pharmacokinetics and pharmacodynamics of azosemide in rats

The circadian changes in the pharmacokinetics and pharmacodynamics of azosemide were investigated after intravenous and oral administration of the drug (10 mg kg(-1)) to rats at 1000 or 2200 h. After intravenous administration of azosemide the percentage of the dose excreted in 8-h urine as unchanged azosemide was significantly higher in the 1000 h group than in the 2200 h group (41.7 compared with 28.9%) and this resulted in a significant increase in 8-h urine output (84.7 compared with 36.6 mL/100 g). After intravenous administration the time-averaged renal clearance (CLR) of azosemide was significantly faster (2.86 compared with 1.76 mL min(-1) kg(-1)) and urinary excretion of sodium (46.4 compared with 25.9 mmol/100 g) and chloride (35.6 compared with 18.8 mmol/100 g) increased significantly in the 1000 h group. However, after oral administration, the percentages of oral dose of azosemide excreted in 8-h urine as unchanged azosemide were significantly higher (1.88 compared with 0.67%) and the CL(R) of azosemide was significantly faster (3.64 compared with 0.79 mL min(-1) kg(-1)) in the 2200 h group. This could be at least partly because of increased absorption of azosemide from the gastrointestinal tract in the 2200 h group; the percentages of oral dose of azosemide recovered from the gastrointestinal tract in 8 h as unchanged azosemide was significantly smaller (5.7 compared with 13.2%) in the 2200 h group. The pharmacodynamic parameters of azosemide were not significantly different after oral administration of the drug to both groups of rats. If these data could be extrapolated to man, the intravenous dose of azosemide could be modified on the basis of circadian time.     

Effect of age on pharmacokinetics and pharmacodynamics in man

Elderly patients represent an increasing part of our population who consume disproportionately high amounts of drugs. During aging physiological and disease-induced changes occur which might affect PK and/or PD of many drugs. The calcium channel blocker verapamil and the benzodiazepine midazolam were taken as examples to illustrate some problems and open questions in research pertaining to the elderly. Following an acute i.v. dose of racemic verapamil and during steady-state (120 mg bid p.o.) no significant differences of the stereoselective disposition of S- and R-verapamil could be found between younger and older healthy subjects. Concomitant intake of rifampicin (600 mg/die) induced especially the presystemic (prehepatic) metabolism of verapamil so that oral bioavailability approached zero and PD effects almost diminished. Intestinal metabolism and inducibility were well preserved in the elderly. The PK and PD of midazolam were investigated in young and older patients who received an i.v. bolus of 0.05 and 0.03 mg/kg, respectively, for premedication prior to third molar teeth extraction. Again, no significant differences in the PK parameters were found between both groups. However, the sedative effects were much more pronounced in the elderly and this population demonstrated a significantly higher CNS-sensitivity to midazolam. All physicians should be aware that for various reasons drug response can be age-dependent and therefore more PK-PD data are needed for the elderly.     

Comparative pharmacokinetics and pharmacodynamics of remifentanil, its principle metabolite (GR90291) and alfentanil in dogs

Remifentanil is an esterase-metabolized opioid developed for use in anesthesia. The principal metabolite of remifentanil, GR90291, is considered to be less potent. This study determined the relative potency of GR90291 and alfentanil, compared with remifentanil, in anesthetized dogs. Male dogs received thiamylal sodium, and anesthesia was maintained using isoflurane and N2O in oxygen. Each dog received a 5-min infusion of 0.5 microg/kg/min remifentanil, 500 microg/kg/min GR90291 and 1.6 mg/kg/min alfentanil in random order, separated by 1 week. Serial blood samples were collected during and after the infusion. The electroencephalogram was evaluated using aperiodic analysis. The pharmacokinetics and pharmacodynamics of remifentanil, GR90291 and alfentanil were determined using nonlinear least-squares regression analysis. Remifentanil was rapidly eliminated, with a terminal half-life of 6 min, compared with 19 min for GR90291 and alfentanil. Using the estimated concentration that elicits 50% of the maximum response (EC50) for delta EEG activity and spectral edge95, remifentanil was 4213 to 4637 times more potent than GR90291 and 7.7 to 8.5 times more potent than alfentanil. The blood-brain equilibration half-life was 2.3 to 5.2 min for remifentanil, 0.39 to 0.41 min for GR90291 and 3.1 to 3.7 min for alfentanil.     

Influence of gender on the pharmacokinetics and pharmacodynamics of drugs

Historically, women, the elderly, and minorities were underrepresented in clinical drug trials. Information on possible gender-related differences in the pharmacokinetics of drugs is often lacking, although for some drugs significant differences could be demonstrated. In women, absorption, protein binding, volume of distribution, and metabolism of drugs may differ due to hormonal influences on physiological functions. Sex-related differences could be shown for phase I (cytochrome P450) as well as phase II (especially glucuronidation) reactions. Since many women world-wide take oral contraceptives, data should be provided to determine to what extent other drugs are influenced by estrogens and progestogens or to what extent the other drugs may attenuate the contraceptive efficacy. Moreover, estrogens interact with various enzymes and receptors, e.g. at the endothelial function as well as dopaminergic receptor sites, and may therefore attenuate or enhance drug effects or even drug side-effects. For a number of drugs it is well recognized, that women suffer more frequently from side-effects, however, it is often not clear, if this is due to gender differences in the pharmacokinetics or pharmacodynamics of the responsible drug. Very little is known about these gender-related differences and the possibility that women may show a different pattern of treatment response than men. As a result, drug approval authorities now require more data on the pharmacokinetics of novel drugs in women as well as a sufficient accrual of women in efficacy and outcome trials.     

Influence of aging on the pharmacokinetics and pharmacodynamics of doxacurium

OBJECTIVE: Different sets of diagnostic criteria have been proposed for Sj?gren's syndrome (SS), but none have been validated with a large series of patients or in a multicenter study. We conducted the present study involving 26 centers from 12 countries (11 in Europe, plus Israel), with the goals of reaching a consensus on the diagnostic procedures for SS and defining classification criteria to be used in epidemiologic surveys and adopted by the scientific community. METHODS: The study protocol was subdivided into two parts. For part I, questionnaires regarding both ocular and oral involvement were developed; they included 13 questions and 7 questions, respectively. For part II a limited set of diagnostic tests was selected, and the exact procedure to be followed in performing these tests was defined. Part I of the study included 240 patients with primary SS and 240 age- and sex-matched controls. Two hundred forty-six patients with primary SS, 201 with secondary SS, 113 with connective tissue diseases but without associated SS, and 133 control patients were studied in part II. RESULTS: The study resulted in (a) the validation of a simple 6-item questionnaire for determination of dry eyes and dry mouth, which showed good discriminant power between patients and controls, to be used in the initial screening for sicca syndrome; and (b) the definition of a new set of criteria for the classification of SS. The sensitivity and specificity of the criteria in correctly identifying patients with either the primary or the secondary variant of SS were also determined. CONCLUSION: Using the findings of this prospective multicenter European study, general agreement can be reached on the diagnostic procedures to be used for patients with SS. Final validation of the preliminary classification criteria for SS is underway.     

Effect of valproate on the pharmacokinetics and pharmacodynamics of lorazepam

The pharmacokinetic-pharmacodynamic interaction between valproate and lorazepam was evaluated in this randomized, double-blind, placebo-controlled crossover study. Sixteen healthy male volunteers enrolled in the study to receive either divalproex sodium (500 mg every 12 hours) or matching placebo for 12 days in the first period, and then to receive the other regimen for an identical second 12-day period. In both periods, lorazepam (1 mg every 12 hours) was administered on days 6 through 9 and on the morning of day 10. Concomitant administration of divalproex sodium with lorazepam resulted in an 8%, 20%, and 31% increase in steady-state maximum plasma concentration, area under the concentration-time curve, and trough plasma concentrations of lorazepam, respectively. The apparent clearance of lorazepam through the formation of lorazepam glucuronide was reduced by 31% during coadministration of divalproex sodium. Pharmacokinetic properties of valproate did not change significantly in the ten available participants during coadministration of lorazepam. Sedation scales revealed no statistically significant differences in sedation between the two regimens. It is concluded that valproate increases plasma concentrations and reduces clearance of lorazepam, most likely by impairing hepatic glucuronidation, and that coadministration of lorazepam does not affect the steady-state pharmacokinetic properties of valproate.