Total and free serum haloperidol levels in schizophrenic patients and the effect of age thioridazine and fatty acid on haloperidol-serum protein binding in vitro.

1 Using radioimmunoassays, steady-state levels of total and free haloperidol (obtained by ultrafiltration and dialysis) have been determined in twenty-two patients on long term treatment receiving doses from 3 to 45 mg per day. 2 For the group, both total serum concentration and free drug concentration showed significant correlations (P less than 0.001) with daily dose. 3 No significant correlation was observed between age of the patient and percentage free haloperidol in serum. 4 In vitro experiments using sera from twenty-three healthy volunteers showed significant negative correlations (P less than 0.01) between age and percentage free haloperidol. 5 Thioridazine and oleic acid significantly enhanced the percentage of free haloperidol in normal human sera in vitro.     

Protein binding of valproic acid in Japanese pediatric and adult patients with epilepsy.

The binding of valproic acid to serum proteins in pediatric and adult patients was studied. Serum samples were obtained from 48 Japanese pediatric patients with epilepsy (group A) and 48 Japanese adult patients with epilepsy (group B) receiving valproic acid monotherapy. The patients' age ranged from 1 to 15 years for the pediatric patients and from 18 to 44 years (group B--younger) and 45 to 63 years (group B--older) for the adult patients. The serum concentrations of total and unbound valproic acid were measured by fluorescence polarization immunoassay, and the unbound serum fraction of valproic acid was analyzed by ultrafiltration. The mean association constant, K, and total concentration of binding sites, n(P), were as follows: group A, K = 0.016 L/mumol, n(P) = 1077 microM; group B, K = 0.011 L/mumol, n(P) = 1365 microM; group B--younger, K = 0.013 L/mumol, n(P) = 1291 microM; and group B--older, K = 0.006 L/mumol, n(P) = 1827 microM. Significant differences between groups A and B were observed in the serum free fatty acid concentration and the serum concentration ratio of free fatty acids to albumin. However, no significant differences between the two groups were observed in the binding of valproic acid to serum proteins. Group A's serum concentration ratio of free fatty acids to albumin was significantly lower than in group B--older and was lower than in group B--younger. However, there were no significant differences in binding between group A and groups B--younger and B--older. The serum concentration of albumin was significantly higher in group B--younger than in group B--older. Consequently, there was a significant difference in binding between groups B--younger and B--older. The serum protein binding of valproic acid was similar in pediatric and adult patients with epilepsy, but binding characteristics differed between younger and older adults.     

Parkinsonism in Elderly Users of Haloperidol: Associated With Dose, Plasma Concentration, and Duration of Use

ABSTRACT: Factors that influence the variation in occurrence of antipsychotic-induced parkinsonism (AIP) in the elderly have not been well elucidated. The aim of this study was to investigate the association between parkinsonism in elderly users of haloperidol and prescribed dose, plasma concentration, and duration of use of haloperidol in a cross-sectional design. This study included 150 inpatients aged 65 years and older who were treated with haloperidol. Parkinsonism assessed by the Simpson Angus Scale was present in 46% of the included patients. Prescribed haloperidol dose varied from 0.3 to 5 mg/d. Plasma concentration ranged from 0.13 to 4.11 μg/L, with one outlying measurement (21.43 μg/L). Dose is moderate but significantly associated with haloperidol plasma concentration (weighted R = 0.32; P < 0.001). Variability in the total score on the Simpson Angus Scale could not be explained by the variability in dose, concentration (respectively R = 0.003 and 0.001) nor duration of use of haloperidol. Smoking showed to be not significantly protective in the development of AIP (crude odds ratio, 0.39; 95% confidence interval, 0.15-0.997; and adjusted odds ratio, 0.44; 95% confidence interval, 0.17-1.17). In a clinical practice-setting dose, neither plasma concentration nor duration of use of haloperidol is associated with an increased occurrence of AIP. This study does not support the hypothesis of the peripheral pharmacokinetic explanation for the high prevalence of AIP and differences in AIP sensitivity in the elderly during treatment with haloperidol.     

Serum levels of clomipramine and desmethylclomipramine and clinical improvement in panic disorder

Several placebo-controlled trials have shown the efficacy of clomipramine (CMI) in panic disorder. However, none has investigated the relationship between CMI, and desmethylclomipramine (DCMI) plasma levels, and outcome. In this trial, 41 patients meeting the DSM-III-R criteria for panic disorder with/without agoraphobia received 50-200 mg of CMI daily in a single-blind, flexible dose regimen for 14 weeks. At the end of treatment, 97% of the patients were free of panic attacks. Patients were classified into two groups of improvement according to the panic symptom items of the 'Patient-Rated Anxiety Scale'. A repeated-measures analysis of variance suggested a significant association between outcome and serum DCMI level/daily dose ratio as well as total serum level/daily dose. Patients with intense improvement showed DCMI and total serum levels lower than those with moderate improvement. The results indicate the importance of monitoring clomipramine and desmethylclomipramine serum levels in this disorder.     

Epidemiologic investigation of the relative clearance of haloperidol by mixed-effect modeling using routine clinical pharmacokinetic data in Japanese patients

The steady-state trough concentrations of haloperidol were studied to clarify the role of the characteristics of Japanese patients in estimating haloperidol dosing regimens by using routine therapeutic drug-monitoring data. Nonlinear mixed-effects modeling (NONMEM) was used to estimate the effect of a variety of developmental and demographic factors on haloperidol clearance values using 270 serum level measurements obtained from 191 patients during their clinical course. The final model describing haloperidol's relative clearance was CL = 0.74 x TBW(0.594) x DOSE(0.326) x 1.32CO1 x 0.867AGE, where CL is clearance (measured in liters per hour), TBW is the total body weight (in kilograms), DOSE is the daily dose of haloperidol (in grams per kilogram per day), CO1 = 1 for concomitant administration of antiepileptic drugs (phenobarbital, phenytoin, or carbamazepine) and CO1 = 0 otherwise, and AGE = 1 for patients aged 55 years or older and AGE = 0 otherwise. Concomitant administration of haloperidol and antiepileptic drugs resulted in a 32% increase in haloperidol clearance. Patients aged 55 years or older showed a 13.3% reduction in clearance values compared with the younger population.     

Pharmacokinetics of the new antiplatelet agent 2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine in human subjects.

The pharmacokinetics of KC-764 (2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine, CAS 94457-09-7) was studied in healthy male adult volunteers after single ascending oral dose and multiple dosing for 7 days. Serum KC-764 concentration attained the peak in 1 h and declined with a half-life of about 2 h at a single oral dose of 5, 10, 20 and 40 mg. No dose dependent pharmacokinetics of KC-764 was demonstrated. Three metabolites were detected in serum, but their concentrations were lower than that of KC-764. 48-h urinary recoveries after single doses were 41.6-46.6% of dose, not being dose-dependent. Urinary recovery of unchanged KC-764 was 1.1-1.6% of dose. Three metabolites were present in greater amount in urine than unchanged KC-764 and two metabolites were less than KC-764. There was little daily variation of serum concentrations and urinary excretion of KC-764 and its metabolites in the multiple dosing (20 mg twice a day) study. The daily and total urinary recovery were same as those after single doses. Food reduced Cmax and tended to delay tmax, but did not influence AUC0----infinity and urinary recovery. Serum protein binding of KC-764 was about 60%, being not dependent on total serum concentration.     

Salicylate protein binding in serum from young and elderly subjects as measured by diafiltration

Summary The protein binding of salicylate was measured by continuous ultrafiltration (diafiltration) at 22°C in serum obtained from 5 healthy young (mean age: 27 years) and 5 healthy elderly (mean age: 73 years) male volunteers. Unbound salicylate increased disproportionately with increasing total salicylate concentration, up to 7000 µmol, in all sera. The fraction bound of salicylate was significantly lower in sera from elderly but this was not due to decreased albumin or total protein concentrations. The binding of salicylate to serum proteins was characterized by two classes of binding sites. The high affinity site had an association constant of either 94901/mol (young) or 75601/mol (elderly) and the number of binding sites was either 4.7 (young) or 3.7 (elderly). The total binding capacity of the low affinity site, 1121/mol, in sera from elderly was significantly less than the binding capacity, 631l/mol, in sera from young. Differences in binding capacity of the low affinity site partially accounted for a two to three-fold increase in the salicylate free fraction in elderly sera. These data suggest that age-related differences in serum protein binding may influence salicylate pharmacokinetics.     

Comparative pharmacokinetics of coumarin anticoagulants. XIV: relationship between protein binding, distribution, and elimination kinetics of warfarin in rats.

The relationships between the protein binding, distribution in the body, and kinetics of elimination of warfarin were studied. Individual rats eliminated warfarin by apparent first-order kinetics, with a biological half-life of 5.9-41 hr and a total plasma clearance of 2.4-22 ml kg(-1) hr(-1). There is a strong positive correlation between the apparent volume of distribution (Vd) and the elimination rate constant (kel). There was no apparent concentration dependance of warfarin binding to serum proteins over a wide concentration range, but there were pronounced intersubject variations in protein binding, with the free fraction of drug (f) in serum ranging from 0.172 x 10(-2) to 1.53 x 10(-2). There are strong positive correlations between f and kel, f and Vd, and f and the kidney-serum concentration ratio of warfarin. Consistent with theory, there is an excellent positive linear correlation between f and total plasma clearance of the drug. The intersubject variation in f is not related to variations in serum albumin or total protein concentration. There is a strong correlation between values of f for serum and liver homogenate in individual animals, consistent with the lack of correlation between f in serum and the liver-serum concentration ratio of warfarin. These results show that the pronounced intersubject variation in the elimination of warfarin observed in this investigation was related to interindividual differences in plasma protein binding of the drug. The differences in protein binding cannot be ascribed to differences in plasma protein concentrations and may reflect configurational differences of proteins or the presence of an endogenous displacing agent at different concentrations.     

Serum, tear and salivary concentrations of methotrexate in man.

1. Methotrexate handling has been studied in four patients with psoriasis and eleven patients with neoplastic disease. 2. Methotrexate levels in serum, tears and saliva were measured by radioimmunoassay while protein binding studies were performed by continuous ultrafiltration. 3. There was a close correlation between methotrexate concentrations in tears and serum (P less than 0.001, r = 0.714). Parotid salivary and serum methotrexate levels were similarly correlated (P less than 0.001, r = 0.557) but not mixed salivary and serum levels (P greater than 0.1, r = 0.232). 4. The mean protein binding was 95.11% +/- 2.26 (s.d.) while the ratio of methotrexate levels in tears to the free serum methotrexate level was 1:1.04. The corresponding parotid salivary level: free serum level ratio was 1:18.11. 5. No relationship could be determined between the methotrexate levels in tears and conjunctivitis observed in some of the patients under study.     

Acute extrapyramidal side effects: Serum levels of neuroleptics and anticholinergics

An assay technique for measuring anticholinergic drugs in human serum based upon their inhibition of the specific binding of [³H]-quinuclidinyl benzilate to rat brain muscarinic receptors is described. The assay was validated by demonstrating a close correlation (r=0.99) between serum levels of nortriptyline measured by the radioenzymatic assay and a GLC technique. The assay measures free anticholinergics, and under standard assay conditions, approximately 95% of benztropine is bound to serum protein. Marked variation in serum anticholinergic levels in patients receiving the same oral dose was observed, and in individual patients there was a non-linear relationship between increasing oral dose and serum anticholinergic levels.In a cross-sectional study of 109 patients receiving concurrently neuroleptics and antichlinergics, there was no correlation (r=0.029) between serum neuroleptic levels measured by a radioreceptor assay and extrapyramidal side effects (EPS). In the patients whose serum anticholinergic levels were also determined, there was a significant inverse correlation (r=0.44) between anticholinergic levels and EPS. In this cohort of patients, there was no significant correlation between serum anticholinergic and serum neuroleptic levels (r=0.16) and the ratio of serum anticholinergic to serum neuroleptic was a poor predictor of EPS (r=0.26).The results suggest a marked variation in sensitivity of patients to the EPS-inducing of neuroleptics; nevertheless, the incidence of EPS decreases with increasing serum levels of anticholinergics. An optimal serum anticholinergic level of 10 pmole atropine equivalent per ml was associated with a low incidence of EPS and is relevant to drug action at the striatal muscarinic receptor.     

Interpatient and intrapatient variability in phenytoin protein binding

The authors retrospectively assessed the relation between total and free serum concentrations and serum albumin in a sample of hospitalized patients to evaluate how well free serum concentrations can be estimated from total phenytoin serum concentrations. The authors also assessed the interpatient and intrapatient variability of the phenytoin free fraction. Paired serum samples of total and free phenytoin serum concentrations and serum albumin were obtained from 48 hospitalized patients (28 males, 20 females; mean age, 51 y; range, 13-90 y). Concomitant medications were recorded. Phenytoin free fraction and adjusted total phenytoin serum concentrations (adjusted for serum albumin) were calculated. One hundred sixty-three samples were obtained (mean, 3.4 samples per patient; range, 1-16 samples); 28 patients had more than one pair of samples obtained. Mean phenytoin free fraction was 15% +/- 7% (range, 4%-61%) for the 163 samples. The variability for the total, free, and free fractions were 65%, 75.9%, and 45.8%, respectively. There was significant variability in the phenytoin free fraction within individual patients who had more than one pair of serum concentrations obtained. The intraindividual coefficient of variation in phenytoin free fraction was 85% +/- 21.3% (range, 2%-94%). Despite strong overall correlation between the total phenytoin serum and free serum concentrations, there is excessive variability in phenytoin protein binding. Correction for serum albumin was not useful in this patient group. Because of significant interpatient and intrapatient variability in phenytoin serum concentrations, monitoring of total serum concentrations is unreliable and free phenytoin serum concentrations should be considered for monitoring in hospitalized patients.     

THE PROTEIN BINDING AND ELIMINATION OF METHOTREXATE AFTER INTRAVENOUS INFUSIONS IN CANCER PATIENTS

Total serum concentrations and protein binding of methotrexate (MTX) have been studied after fifty-eight 6 h MTX infusions in nineteen cancer patients. 1. There was a linear relationship between dose (mg/kg) and serum MTX concentration at termination of infusion. 2. The elimination of total serum and ‘free’ MTX followed similar bi-exponential expressions during the 72 h studied after the infusion. 3. Of the eight occasions when total serum concentrations did not fall below 10^?7 mol/l on the third day, five were associated with toxicity. 4. Mean per cent MTX bound by sera from the nineteen patients was 47.2 (s.d. = 4.4) per cent and appeared to be independent of MTX concentration within the range studied. 5. This study suggests that the very high binding previously reported for MTX should be questioned and that measurement of total serum MTX concentration (bound plus free) is sufficient for the recognition of patients who might be at risk of developing toxicity.     

Interindividual variation of plasma haloperidol concentrations and the impact of concomitant medications: the analysis of therapeutic drug monitoring data

We analyzed therapeutic drug monitoring (TDM) data from 231 schizophrenic inpatients (137 men, 94 women) and investigated interindividual differences of plasma haloperidol (HAL) concentrations and drug/drug interactions between HAL and various concomitant drugs. Plasma HAL concentrations were determined by an enzyme immunoassay (EIA) method. Plasma HAL concentrations per daily dose of HAL per body weight (HAL C/D ratio) demonstrated an approximately 11-fold interindividual variation. The patient subjects who received carbamazepine (CBZ) concomitantly had a mean HAL C/D ratio that was 37% lower than that of the patient subjects without CBZ. The patient subjects treated with concomitant phenobarbital (PB) also showed a mean HAL C/D ratio that was 22% lower than those without PB. We concluded that careful evaluation of HAL TDM data and consideration of the impact of concomitant medication such as CBZ or PB that might influence the metabolism of HAL is necessary in daily clinical settings to avoid insufficient clinical response because of lowered concentrations of HAL or adverse effects because of high concentrations of HAL.     

Clinical implications of serum protein binding in epileptic children during sodium valproate maintenance therapy

Steady-state serum levels of total and unbound valproic acid as well as unbound fraction in epileptic children were studied in a clinical setting. Valproic acid binding parameters were analyzed and compared with in vitro findings. Daily dose of sodium valproate ranging from 29 to 73 mg/kg/day were administered per os. Considerable variation in total and unbound concentrations and unbound fractions within and between subjects was observed. In subjects evaluated in this study, serum level of total and unbound valproic acid ranged from 279 to 1,196 mumol/L and from 37 to 410 mumol/L, respectively. The unbound fraction ranged from 10.32 to 48.39%. In vivo binding parameters obtained from clinical material were as follows: association constant, Ka = 4.984 L/mmol; total binding sites, NP = 1.451 mmol/L, where P is the molar concentration of albumin; number of binding sites per molecule of albumin, N = 2.48. Using spiked sera, binding parameters of Ka = 8.032 L/mmol, NP = 1.262 mmol/L, and N = 1.86 were found in the in vitro study. The association constant obtained from in vivo and in vitro studies were not significantly different (p greater than 0.05) from each other. The unbound fraction of valproic acid was concentration dependent even within the therapeutic range. An equation for estimating unbound concentration (Cf') or unbound fraction (fp') from total concentration (Ct) of valproic acid is derived. The ratio of observed unbound fraction to the estimated unbound fraction (fp/fp') was used to evaluate the variation in valproate serum binding of that clinical sample. Nine samples from hospitalized patients whose medication and diet were closely supervised showed an fp/fp' ratio very close to 1 (mean +/- SD 1.04 +/- 0.24). It is suggested that a clinical sample showing a value of fp/fp' greater than 1.76 (mean + 3 SD) should be evaluated for the cause of the decrease in serum binding and for the associated pharmacokinetic alterations. Therefore, in clinical monitoring of valproate, determination of both total and unbound drug levels was preferable to determination of either one alone. Furthermore, an understanding of the unbound fraction of valproic acid would significantly contribute to the effective management of epileptic patients.     

Relationship between serum concentration and dose of valproic acid during monotherapy in adult outpatients.

The relationship between serum concentration and dose of valproic acid (VPA) is reported to be variable and inconsistent. However, studies evaluating this relationship have included individuals of varying ages and patients receiving potentially interacting medications. In this study, the relationship between VPA serum concentration and dose was evaluated in a homogeneous patient population. Medical records of 60 adult outpatients with epilepsy receiving VPA monotherapy were examined retrospectively for VPA dose (milligrams per kilogram) and corresponding serum VPA concentrations. A significant linear correlation was found in the relationship between VPA dose and serum concentration among all patients (r = 0.63; p less than 0.01). However, considerable interindividual variability in this ratio was demonstrated [coefficient of variation (CV) = 28.9%], and the ratio was significantly dependent on VPA dose. In three selected individual patients, a significant linear correlation was also demonstrated in the VPA serum concentration:dose relationship over time (r = 0.91, 0.94, 0.96; p less than 0.05 for all three patients) with substantially less variability (CV = 10.2-14.6%) and without significant dose dependency, suggesting that this parameter may be useful for guiding VPA dosage adjustment and monitoring patient compliance. Further study is required to evaluate the utility of the serum concentration:dose ratio in monitoring VPA therapy.     

Comparative pharmacokinetics of coumarin anticoagulants. XLIX: Nonlinear tissue distribution of S-warfarin in rats

The serum protein binding of the oral anticoagulant drug warfarin varies widely among rats and largely accounts for corresponding variations in the total serum clearance of the drug. The hepatic uptake of warfarin is concentration dependent despite the concentration independence of the free fraction of warfarin in serum over a wide concentration range. This investigation was designed to determine the distribution of the S enantiomer of warfarin in rats as a function of warfarin concentration, free fraction in serum, dose, and time. Two groups of rats, one with relatively low (0.0043) and the other with relatively high (0.0105) average serum free fraction values, were selected from a large number of adult male Sprague-Dawley rats. All animals received an iv injection of S-warfarin, either 0.25 or 1.0 mg/kg, and were sacrificed at intervals over a period of 10 d. Concentrations of S-warfarin in serum, liver, kidneys, muscle, and fat were determined by HPLC. The tissue:serum concentration ratio (T:S) of the drug was highly concentration dependent, but was independent of dose, time, and (except for fat) free fraction in serum. The T:S for fat was higher in animals with the larger serum free fraction values. The T:S of S-warfarin for the liver was greater than 10 at low concentrations and reached a limiting value of 0.25 at relatively high concentrations of the drug. In general, the T:S versus concentration profiles of S-warfarin are consistent with the presence of two classes of binding sites in the tissues, one with very high affinity and low capacity, the other with lower affinity and apparently unlimited capacity under the experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of protein binding of pilsicainide on the pharmacokinetics

To evaluate the effect of protein binding of pilsicainide on its clearance and the contribution of protein binding to optimized pilsicainide therapy, clinical laboratory and pharmacokinetic data were studied in 160 Japanese inpatients (Study 1) and 18 Japanese inpatients (Study 2). To determine the relation between protein concentration and the protein binding ratio of pilsicainide in vitro, the effect of human alpha1-acid glycoprotein (AAG) and human albumin on the binding ratio was studied. The mean ratio of serum pilsicainide concentration to dose per body weight (C/D) increased with increases in the C-reactive protein (CRP) concentration in Study 1. The AAG level increased with increases in the CRP concentration and the binding ratio increases in the AAG concentration in the Study 2. The binding ratios increased with increased AAG and albumin concentrations; the AAG concentration relative to the ratio was particularly large in vitro study. These results suggest C/D is increased in patients with high CRP levels because of binding of pilsicainide to protein, resulting decreased clearance.     

Effect of serum protein binding on pharmacokinetics and anticoagulant activity of phenprocoumon in rats

The relationship among serum protein binding, kinetics of elimination, distribution, and anticoagulant activity of phenprocoumon was investigated in 25 selected outbred Sprague-Dawley rats which differed in the extent of serum protein binding of this drug. In addition, the serum protein binding of phenprocoumon was altered in inbred Lewis rats by continuous treatment with tolbutamide. This drug was found to displace phenprocoumon from serum proteins without affecting its intrinsic clearance. The serum free fraction values (f_s)of the selected Sprague-Dawley rats ranged from 0.0053 to 0.0145. There were positive and linear correlations between f_s and the first-order elimination rate constant (k), f_s and total clearance (CL _total ),and f_s and the liver/plasma concentration ratio (L/P ratio) of phenprocoumon. The free fraction values in the liver tissue (f _I )showed twofold variations and were not related to f_s.The half-effective plasma concentrations (C _p50% )of total phenprocoumon (i.e., the concentrations necessary to inhibit the prothrombin complex synthesis rate by 50%) decreased with increasing f_s.The C_p50% values of total drug varied eightfold between the animals but those of free drug only 3.5- fold. The total anticoagulant effect per dose (AE/dose), as reflected by the magnitude of the area above the prothrombin complex activity vs. time curve in the plasma, varied only 1.5- fold between the rats and was not related to f_s.Continuous treatment of inbred Lewis rats with tolbutamide led to an increase of f_s (twofold), k (1.3-fold), V_d (1.5-fold), and CL_total (twofold). The intrinsic clearance (CL _intr )remained unaffected. There was no significant increase of f_L but a twofold increase of the L/P ratio. AE/dose and the C_p50% values of free drug in tolbutamide-treated rats were not significantly different from those of control rats. Thus an increase of the free fraction of phenprocoumon in the serum of rats is followed by a proportional increase of the total clearance. This prevents a concomitant rise of the free drug concentration. Consequently, the total anticoagulant effect per dose remains almost unaffected by about threefold variations in the serum free fraction values of this drug.This work was supported by the Deutsche Forschungsgemeinschaft: it is part of the Ph.D. thesis for D. T.     

Effect of glycated albumin on phenytoin binding in elderly patients with type II diabetes mellitus

We evaluated the effect of glycated albumin on phenytoin protein binding in 36 elderly (age range 63-94 yrs) patients with type II diabetes mellitus (DM) under diet management. Serum was spiked with 15 mg/L phenytoin and incubated. A serum ultrafiltrate was obtained from each sample for determining total and free phenytoin concentrations. Glycated hemoglobin was determined by boronate-affinity chromatography, and glycated albumin was separated from nonglycated fractions with boronate-agarose gel. Glycated hemoglobin in the study group ranged from 4.3-14.6% (mean 7.8 +/- SD 2.1%) and glycated albumin ranged from 3.7-12.5% (7.4 +/- SD 2.6%). We observed no correlation between glycated albumin and the percentage of free phenytoin (r2 = -0.14; p = 0.419). The concentration of nonglycated albumin ranged from 0.66-4.28 g/dl (mean 3.45 +/- 0.67 g/dl) and was calculated from measured total and glycated albumin concentrations. A correlation between the free fraction of phenytoin and nonglycated albumin was not demonstrated (r2 = 0.22, p = 0.22). In addition, a correlation was not observed between total glycated albumin and the free fraction of phenytoin (r2 = -0.095; p = 0.58). We conclude that elderly patients with type II DM under diet control do not have significant alterations in phenytoin protein binding. The use of total serum phenytoin levels therefore appears appropriate for determining phenytoin dosages in elderly patients with well controlled type II DM.     

Pharmacokinetics of haloperidol in psychotic patients

Nine psychotic patients under continuous oral treatment with haloperidol were randomly given a test dose of 1.5–5 mg haloperidol orally and/or intravenously. Serum levels of haloperidol were determined by high performance liquid chromatography and serum concentration data obtained were submitted to pharmacokinetic analysis. The steady state concentration ratio between blood and plasma was determined and found to be 0.79±0.03. The blood clearance was then calculated to be 550±133 ml/min. The mean hepatic extraction ratio was intermediate (0.37). Consequently, for a drug mainly eliminated by hepatic metabolism like haloperidol, the total blood clearance and the extent of oral bioavailability can be affected by changes in hepatic blood flow, hepatic enzyme activities and drug binding. During continuous oral treatment with haloperidol, however, it can be shown that changes in the total metabolic capacity of the liver due to hepatic enzyme induction or inhibition should be important for the therapeutic effects of haloperidol. The volume of distribution at steady state (Vdss) was large (7.9±2.5 l/kg). The terminal half-life was 18.8 h after intravenous and 18.1 h after oral administration. The oral bioavailability (0.60±0.18) were in accordance with previous results in healthy subjects. A mean lag time after oral dose was 1.3±1.1 h and a longer absorption half-life (1.9±1.4 h) was found in the patients compared with healthy volunteers.