Pharmacokinetics of diazepam in epileptic patients and normal volunteers following intravenous administration

1 The pharmacokinetics of diazepam following intravenous administration have been investigated in six normal volunteers and nine epileptic patients receiving chronic antiepileptic drug therapy. 2 After intravenous administration, serum diazepam levels declined biexponentially in all subjects. The elimination half-life was significantly shorter and the plasma clearance significantly higher in the patients than in the normal volunteers. 3 Serum N-desmethyldiazepam levels were higher and the time to peak serum concentration was earlier in the epileptic patients than in the controls. 4 It is suggested that the metabolism of diazepam is induced in patients treated with enzyme inducing antiepileptic drugs, although a protein binding interaction between valproic acid and diazepam may contribute to the higher plasma clearance in the epileptic patients taking sodium valproate.     

Diazepam kinetics in patients with renal insufficiency or hyperthyroidism.

1 Eight patients with end-stage renal insufficiency on maintenance haemodialysis, and seven patients with newly diagnosed hyperthyroidism, received a single intravenous dose of diazepam, followed by blood sampling over the next 7 days. Fifteen healthy volunteer controls, matched with patients for age and sex, were similarly studied. 2 Diazepam half-life in renal failure patients (mean 37 h) was greatly reduced compared to controls (mean 92 h, P less than 0.05) and clearance of total (free plus bound) diazepam correspondingly increased (0.94 v 0.34 ml min-1 kg-1, P less than 0.01). 3 However, differences were largely related to disease-related changes in drug binding and distribution. Mean unbound fraction of diazepam in plasma of renal patients (7.0%) was greatly increased over controls (1.4%, P less than 0.01) and Vd of unbound diazepam greatly reduced (57 v 157 l/kg, P less than 0.01). 4 Clearance of pharmacologically active unbound diazepam (intrinsic clearance) was not significantly different between renal patients and controls (23 vs 30 ml min-1 kg-1). 5 None of the kinetic variables for total or unbound diazepam in thyrotoxic patients differed significantly from those in controls matched for age and sex. 6 End-stage renal failure (or its associated drug therapy) alters diazepam protein binding and distribution, but does not significantly change clearance of unbound drug. Thyrotoxicosis does not influence diazepam kinetics.     

The kinetics of salivary elimination of cyclophosphamide in man.

1 The concentrations of cyclophosphamide in plasma and saliva were determined in seven patients following administration of single doses of cyclophosphamide during chemotherapy for lymphoma. 2 The saliva/plasma ratio was 0.77 +/- 0.24 (s.d.) and showed no time-dependence being rapidly established following intravenous and oral administration. 3 The T 1/2 of cyclophosphamide (8.38 +/- 2.25 h) determined from salivary measurements was not significantly different from that in plasma (8.24 +/- 2.60 h). It was not possible to estimate the apparent volume of distribution or total body clearance utilizing the salivary cyclophosphamide concentration without appropriate correction for the saliva/plasma concentration ratio. 4 The binding to the plasma protein of normal plasma of cyclophosphamide was 13.4 +/- 5.3%. The Scatchard plot for binding to bovine serum albumin indicates only weak binding to non-specific sites. 5 Salivary cyclophosphamide therefore indicates the concentration of the unbound fraction of plasma cyclophosphamide.     

Pharmacokinetics of diazepam in the rat: influence of a carbon tetrachloride-induced hepatic injury.

The pharmacokinetics of diazepam in normal rats and in rats pretreated with carbon tetrachloride to induce hepatic cirrhosis (cirrhotic rats) was studied after intravenous and oral administration of the drug (4 mg/kg). Animals pretreated with this hepatotoxic agent showed a significant prolongation in the half-life of diazepam in plasma that is due more to an increase in volume of distribution rather than to a decrease in clearance. This study confirmed that diazepam was highly extracted by the rat liver and was not affected by the hepatotoxic agent, although there probably was a saturation of the activity of the cytochrome P450 enzyme when the drug was administered orally. Diazepam binds to plasma proteins to a high degree in both normal and cirrhotic rats; however, in the latter, a significant increase in the fraction of unbound drug in plasma was observed. Pretreatment of rats with carbon tetrachloride did not produce any change either in the distribution of diazepam into erythrocytes or in the disposition of the metabolite desmethyldiazepam.     

Drug interaction. Effects of salicylate on pharmacokinetics of valproic acid in rats

The effects of salicylic acid on the pharmacokinetics of valproic acid were investigated in bile-exteriorized rats. A 50 mg/kg bolus dose of sodium valproate was injected iv to Long Evans rats with and without (control) prior treatment by constant infusion of salicylate to keep it at steady state plasma level (about 250 micrograms/ml). The plasma elimination of valproic acid followed a monoexponential decline in both salicylate-treated and control rats. A significant increase (p less than 0.01) in the disposition rate constant (kel), the volume of distribution (Vd), and the total clearance (Cltot) as well as a significant decrease (p less than 0.01) in the AUC and the elimination half-life (t1/2) were observed in the salicylate-treated rats. In spite of the significantly lowered total plasma level and increased unbound fraction of valproic acid in the salicylate-treated rats, there were no significant differences in unbound valproic plasma levels and unbound valproate pharmacokinetic parameters. The biliary excretion of unchanged and conjugated valproate was not significantly different between the two groups. The in vitro plasma-unbound fractions (fu) of valproic acid were significantly increased (p less than 0.01) in the presence of salicylic acid. The apparent dissociation constant of plasma protein binding for valproic acid was increased from 0.287 to 1.204 mM in the presence of salicylic acid. These findings indicate that the pharmacokinetic changes of valproic acid in the presence of salicylic acid were consistent with the elevation in the plasma-unbound fraction of valproic acid due to displacement from plasma protein-binding sites by salicylic acid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prediction of the disposition of nine weakly acidic and six weakly basic drugs in humans from pharmacokinetic parameters in rats

Various pharmacokinetic parameters--disposition half-life, t1/2,z, metabolic clearance CLm, volume of distribution V, intrinsic clearance of unbound drug CLuint, and unbound volume of distribution of tissues (distributive tissue volume/fraction of drug in tissue unbound, VT/fuT--are compared in rat and human for nine weakly acidic drugs, phenytoin, hexobarbital, pentobarbital, phenylbutazone, warfarin, tolbutamide, valproate, phenobarbital, and amobarbital, and six weakly basic drugs, quinidine, chlorpromazine, propranolol, pentazocin, antipyrine, and diazepam. With regard to all parameters, statistically significant correlations are obtained when parameters are plotted on a log-log plot. Correlation coefficients between the intrinsic parameters (CLuint or VT/fuT) were higher than those between the hybrid parameters (t1/2,z, CLm or V). In general, these drugs were metabolized ten times more rapidly in rat than in human. With regard to the tissue distribution of these drugs, there was little difference between rat and human. Predictions of CLm, V, and t1/2, in humans using rat data were successful for most drugs, with a few marked exceptions.     

Pharmacokinetics of ketoprofen in rats: effect of age and dose.

The effects of age and dose on the pharmacokinetics of ketoprofen were evaluated in young adult and senescent male Fischer 344 rats following intravenous administration of 2.5 and 10 mg kg-1. Plasma concentrations were measured by HPLC and free ketoprofen determined by equilibrium dialysis. The glucuronidation of ketoprofen was investigated in a preparation of rat liver microsomes and kinetic analysis of UDP-glucuronyltransferase was carried out by determining the initial rate of metabolic activity as a function of ketoprofen concentration. Mean plasma clearance CLfree and steady-state volume of distribution Vssfree calculated from unbound plasma ketoprofen concentrations were significantly lower in the aged rat, suggesting reduced metabolic activity and decreased ketoprofen binding to tissue components, respectively. Plasma protein binding demonstrated an age-dependent decline due to decreases in both albumin concentration and binding affinity. Thus, plasma clearance CL and steady-state volume of distribution Vss changes were insignificant when total plasma concentrations were examined, due to the greater free fraction of ketoprofen in the plasma of senescent rats. The maximal rate of ketoprofen glucuronidation by hepatic microsomes was reduced whereas the affinity of the metabolic enzymes for the compound was unaffected by age. Dose had a marked effect on the disposition of ketoprofen as well. Saturation of elimination pathways and tissue binding sites contributed to significant declines in CLfree and Vssfree with increasing dose. Likewise, concentration-dependent plasma protein binding occurred, reflecting saturation of albumin binding. Thus, changes in the pharmacokinetic parameters based on total drug concentrations were offset by the increase in the unbound fraction of ketoprofen.     

The influence of binding to albumin and α1-acid glycoprotein on the clearance of drugs by the liver

The liver is a major site for synthesis and catabolism of plasma proteins. Albumin has various binding sites for anionic drugs,α ₁acid glycoprotein possesses a single binding site for cationic drugs. In spite of extensive protein binding, the liver can efficiently remove drags from the circulation. Intrahepatic dissociation of the drag-protein complex may involve dissociation-limited debinding under non-equilibrium conditions or surface interaction-facilitated dissociation phenomena. During liver or renal disease and acute-phase conditions plasma protein binding of drugs may be affected. Changes in the unbound drag fraction do not always result in proportional changes in clearance or distribution volume. Potential changes in the unbound concentration in steady-state as well as the fluctuations in total plasma levels depend on the extent of protein binding of a drug, the relative change in the unbound drug fraction, type of clearance, the size of the distribution volume, route of administration as well as concomitant changes in intrinsic (cellular) clearance function. Optimization of dosage regimens for certain drags and interpretation of liver function tests with diagnostic dyes may largely benefit from determination of the unbound rather than the total concentration of the drags involved.     

Oxaprozin pharmacokinetics in patients with congestive heart failure

12 patients aged 26-71 years with stable, compensated congestive heart failure (CHF) and 12 healthy controls matched for age, sex, height, weight, and serum albumin, received a 1200-mg oral dose of the nonsteroidal antiinflammatory agent 4,5-diphenyl-2-oxazolepropionic acid (oxaprozin). Serum oxaprozin levels were measured by high pressure liquid chromatography during the next 14 days. Oxaprozin elimination half-life was not different between controls and CHF patients (63 vs 69 h), but peak serum levels were lower (79 vs 63 micrograms/ml, p less than 0.01), apparent volume of distribution was larger (0.22 vs 0.29 l/kg, p less than 0.05) and clearance tended to be higher, although not significantly so, (0.042 vs 0.053 ml/min/kg) in CHF patients. These differences might have been due to reduced serum protein binding (increased free fraction) in CHF patients (0.25 vs 0.44% unbound, p less than 0.1). After correction for individual values of free fraction, groups did not differ in peak free oxaprozin serum levels (0.20 vs 0.26 micrograms/ml), unbound volume of distribution (92 vs 83 l/kg), or unbound clearance (17.5 vs 15.0 ml/min/kg). Thus protein binding of oxaprozin in the present study was reduced in CHF due either to the underlying disease or to the concurrent medications. This in turn caused reciprocal reduction in total (free plus bound) oxaprozin levels and elevated estimates of volume of distribution and clearance. Although protein binding is altered, CHF causes no significant alteration in distribution of free oxaprozin nor free clearance of oxaprozin, which is accomplished by a combination of oxidation and conjugation.     

Estimating unbound volume of distribution and tissue binding by in vitro HPLC-based human serum albumin and immobilised artificial membrane-binding measurements

The in vivo unbound volume of distribution (V(du)) can be used to estimate the free steady-state plasma concentration with a given dose of a drug administered intravenously. We have demonstrated that the calibrated HPLC retention times obtained on biomimetic stationary phases, such as immobilised human serum albumin and phosphatidyl-choline, can be used to estimate compounds' in vivo behaviour. The mechanistic models are based on the assumption that the sum of the albumin and phospholipid binding has the most significant impact on reducing compounds' free concentration both in plasma and in tissues. The model equations were obtained using the literature human volume of distribution and fraction unbound in plasma values of 135 known drug molecules and have been tested on a further 300 in-house compounds. The model can be used to design compounds with low V(du) values and high fraction unbound in tissues which will minimise the required dose to achieve the efficacious free concentration at the target organ (excluding possible active transport processes).     

Naproxen disposition in patients with alcoholic cirrhosis

Summary Chronic liver disease is known to alter the absorption and disposition of many drugs. To assess the influence of chronic alcoholic liver disease on the disposition of naproxen, we administered the drug both as a single dose and to steady state to 10 individuals with alcoholic cirrhosis and to 10 healthy controls. Plasma and serum samples collected after naproxen dosing were assayed for both total and (following equilibrium dialysis) unbound drug concentration. Clearance calculated based on both total and unbound naproxen concentration revealed no change in total plasma clearance of the drug at steady state but a marked reduction of approximately 60% in clearance based on unbound drug. Naproxen volume of distribution changed only minimally. Because clearance based on unbound drug concentration at a given dosing rate determines the plasma or blood free drug concentration, this concentration may increase significantly in patients with alcoholic liver disease given usual doses of naproxen. Unbound drug concentration is thought to determine the pharmacologic effect of a drug. We therefore recommend that naproxen dosing be reduced by at least half in patients with chronic alcoholic liver disease. In the absence of data to the contrary, this recommendation can be extended to individuals with other forms of hepatic disease.     

In vivo interaction of the enantiomers of disopyramide in human subjects

Disopyramide, an antiarrhythmic agent, is marketed as a racemic mixture of two enantiomers. The racemic drug has unusual pharmacokinetic properties because of its concentration-dependent binding to plasma proteins in the therapeutic plasma concentration range. This study examined, in healthy subjects, the individual pharmacokinetic properties of both total and unbound d- and 1-disopyramide in plasma after intravenous administration of each enantiomer separately (1.5 mg/kg). Also investigated is the pharmacokinetics of total d- and 1-disopyramide in plasma after intravenous administration of a pseudoracemate. Both d- and 1-disopyramide are found to exhibit concentration-dependent binding to plasma proteins, with d-disopyramide being more avidly bound at lower concentrations. The stereoselective, concentration-dependent binding to plasma proteins resulted in distinct pharmacokinetic properties when the enantiomers were given together as the pseudoracemate. d-Disopyramide had a lower plasma clearance and renal clearance, a longer half-life, and a smaller apparent volume of distribution than 1-disopyramide. However, when the enantiomers were administered separately, there were no differences in the clearance, renal clearance, and volume of distribution between enantiomers calculated from either total or unbound drug concentrations. The results reveal an important pharmacokinetic interaction between the enantiomers of disopyramide when given as a racemic mixture, which may be dose-dependent and is not apparent upon administration of the enantiomers separately.     

Oxaprozin dose proportionality

Twelve normal subjects each received single 300-, 600-, and 1200-mg oral doses of oxaprozin according to a three-period crossover design. Total drug plasma concentrations did not increase in proportion to the dose administered. Total clearance (CIo) and volume of distribution (Vd) increased with dose, though elimination t1 2 remained unchanged. The fraction of unbound oxaprozin in plasma (fup) varied linearly with total plasma concentration: it increased from 0.068 per cent at 10 micrograms/ml to 0.180 per cent at 170 micrograms/ml. A parameter fup was therefore introduced to express the average degree of unbound drug plasma for a given dose, and to allow the calculation of unbound volume of distribution (Vdu) and intrinsic clearance (CIi) as if binding were constant. Even though fup increased with dose, the overall binding in the body (fub approximately 0.52 per cent) was relatively stable. Neither Vdu nor CIi changed with dose; hence, unbound oxaprozin kinetics can be considered to be linear. Protein binding had no effect on unbound oxaprozin plasma levels within the given dose range, and there was a one-to-one proportionality between the dose administered and the unbound drug concentration in plasma.     

DOSE-DEPENDENT DISTRIBUTION VOLUMES OF TOTAL AND UNBOUND VALPROATE IN GUINEA-PIGS: CONSEQUENCE OF NON-LINEAR PLASMA PROTEIN BINDING

The response of steady-state distribution volume (V_dss for total and V_dssu for unbound drug) of valproate (VPA) to dose-dependent plasma protein binding was studied in guinea-pigs. Various steady-state plasma concentrations of VPA were achieved by intravenous constant infusion. The concentrations of VPA in plasma (C_ss for total and C_uss for unbound drug) and various tissues (C_T) were determined. The V_dss and the V_dssu were estimated based upon the apparent tissue-to-plasma concentration ratio of VPA. The results showed that the plasma unbound fraction (f_u) of VPA increased significantly with dose. The V_dss was significantly increased with, while the V_dssu was significantly decreased against the increasing dose. The increase in V_dss with dose indicated an increase in tissue-to-plasma concentration ratio, which may be attributed to the increase in distribution of unbound drug from plasma to tissues subsequent to non-linear plasma protein binding. The decrease in V_dssu against the increasing dose indicated a decrease in tissue-to-unbound plasma concentration ratio, which suggests that the extravascular distribution of unbound VPA might be capacity limited and the tissue binding of VPA negligible.     

Effect of valproate on free plasma phenytoin concentrations.

The plasma protein binding of phenytoin was studied in nine epileptic patients before and during addition of sodium valproate to the drug therapy. The free phenytoin fraction in plasma was significantly greater during sodium valproate treatment. The mean free fraction rose from 0.135 +/- 0.019 (s.d.) to 0.182 +/- 0.030. Total plasma phenytoin concentration fell significantly from a range of 4.3-26.2 micrograms/ml to 3.4-19.8 micrograms/ml during sodium valproate treatment. Neither the free plasma concentration nor the saliva concentration of phenytoin was significantly altered by sodium valproate. No significant correlation was found between plasma valproic acid concentrations and the change in phenytoin binding. We conclude that valproic acid displaces phenytoin from plasma protein binding sites but does not inhibit its metabolism.     

Effect of heparin administration on plasma binding of benzodiazepines.

1 The effect of intravenous administration of 100 units of heparin on plasma of diazepam, chlordiazepoxide, oxazepam and lorazepam was examined in fourteen normal subjects and five patients with cirrhosis. 2 In normal non-fasted subjects heparin caused a rapid 150--250% rise in the free fraction of diazepam, chlordiazepoxide and oxazepam but no change of lorazepam. The changes in free fraction were slightly smaller, but still significant, when the subjects were fasted. 3 These change in free fraction occurred within 90 s of administration of heparin and binding had returned to baseline by 30 to 45 min. 4 In the cirrhotic subjects the response to heparin was variable. 5 The use of heparin during drug disposition studies may affect the estimation of pharmacokinetic parameters and possibly pharmacological effects which are dependent on the circulating unbound drug level.     

Cortisol does not inhibit prednisolone clearance.

The disposition of prednisolone has been studied in eight male subjects with and without the concomitant administration of cortisol which produced plasma cortisol concentrations 10-fold higher than endogenous levels. The clearance and steady-state distribution volume of total prednisolone were increased as was the prednisolone free fraction but the clearance of unbound prednisolone was unaltered by cortisol co-administration.     

Differential effects of valproic acid on the serum protein binding of lorazepam and diazepam

Valproic acid and free fatty acids have been shown to displace diazepam from its plasma binding sites both in vitro and in vivo. Since lorazepam exhibits a substantial degree of binding, but differs from other benzodiazepines in that no increase in its free fraction in serum is observed when free fatty acids are raised, the effect of valproate on the serum protein binding of diazepam and lorazepam was assessed. Sodium valproate produced a marked increase in the free fraction of diazepam, but practically no effect on the percentage of free lorazepam.     

Pharmacokinetics of quinidine related to plasma protein binding in man

Summary The disposition and plasma protein binding of quinidine after intravenous administration were studied in 13 healthy subjects. Plasma protein binding, expressed as the fraction of quinidine unbound ranged from 0.134–0.303 (mean 0.221). Elimination rate constant () varied from 0.071 to 0.146 h^–1 (mean 0.113), and apparent volume of distribution (V) varied from 1.39–3.20 l · kg^–1 (mean 2.27). Total body clearance was 2.32–6.49 ml min^–1 · kg^–1. There was a positive linear correlation between the plasma fraction of unbound quinidine and both V (r=0.885, p<0.01) and total body clearance (r=0.668, p<0.05). No significant correlation existed between the fraction of unbound quinidine in plasma and the elimination rate constant. The results show that both the apparent volume of distribution and total body clearance of quinidine are proportional to the unbound fraction in plasma. This implies that the total plasma concentration of quinidine at steady state will change with alterations in plasma binding, whilst the concentration of unbound compund and its elimination rate will remain unaffected.     

Theophylline pharmacokinetics in advanced age.

1 Theophylline kinetics following a single oral dose were characterized and compared in non-institutionalized ambulatory elderly and young gender-matched control subjects. Study design stressed stringent, yet realistic, control of several external factors known to influence theophylline metabolism. 2 Plasma levels of total drug were significantly higher in the elderly only at early sampling times (0.5 and 1 h) and at 36 h, while unbound theophylline levels were significantly higher (P less than 0.05) at all sampling times resulting in a 45% greater AUC for unbound drug. 3 While no significant differences in volume of distribution (Vd) or overall plasma clearance were observed when calculations were based on total plasma theophylline, a 37% reduction in Vd (P less than 0.005) and a 30% reduction in overall plasma clearance (P less than 0.02) in the elderly became apparent when plasma protein binding was taken into account. 4 When urinary excretion patterns were compared, the elderly were found to have excreted a significantly higher fraction of the recovered dose as 1-methyluric acid (P less than 0.01) and a lower fraction as unchanged theophylline (P less than 0.02). A 47% reduction in the renal clearance of unbound theophylline (P less than 0.005) was also observed in the elderly. 5 Results were consistent with less viable metabolism and renal excretion pathways for theophylline elimination in the elderly and serve to reemphasize the importance of including an assessment of plasma protein binding in studies of drug disposition in the elderly.