Mianserin protein binding in serum and plasma from healthy subjects and patients with depression and rheumatoid arthritis

Mianserin protein binding was measured in serum from 43 healthy subjects and plasma from 12 elderly depressed patients and 23 patients with rheumatoid arthritis. Free fraction (mean±SD) was 5.5±0.7% in the healthy subjects, 5.0±0.8% in the elderly subjects and 6.0±1.0 in the patients with rheumatoid arthritis. In the group of elderly patients treated with mianserin, a high correlation (r=0.83, P<0.001) between total and free concentrations of mianserin was found. In both groups a high linear correlation (r=+0.90, P<0.001) between the free fraction of mianserin and that of imipramine was found, the latter being about twice as high as for mianserin.In both healthy subjects and arthritis patients the degree of protein binding was positively correlated to the concentration of ₁-acid-glycoprotein and complement C3_c, and somewhat more weakly to haptoglobin. In the healthy subjects protein binding was also highly positively correlated to the concentration of apolipoprotein B, whereas no such correlation was found in the rheumatoid arthritis patients. In the rheumatoid arthritis patients protein binding was highly correlated to the concentration of hemopexin and somewhat more weakly to ceruloplasmin and fibrinogen; a weak negative correlation to the concentration of albumin was also found. Since significant intercorrelations between the concentrations of these proteins were found, the correlation to the degree of binding of mianserin may not necessarily represent binding of the drug to the protein.     

The influence of blood collection technique on serum and plasma protein binding of disopyramide

Summary Serum and plasma disopyramide (D) protein binding was compared after blood was collected from four normal subjects in various Vacutainer^® tubes. The fraction of disopyramide bound to proteins in control serum and plasma was drug concentration dependent and correlated well with the capacity factor (N) associated with a high affinity protein binding site. D free fraction increased 60% at a post-equilibrium concentration of 2 µg/ml in plasma following exposure of blood to green-top Vacutainer^® stoppers due to a 60% reduction in the affinity constant associated with the high affinity protein binding site. Heparin and EDTA had no effect on the plasma protein binding of D. These results suggest a competitive inhibition of disopyramide binding to ₁-acid-glycoprotein following contact of blood with rubber Vacutainer^® stoppers.Sponsored by Grant GM-28424-01 from the National Institutes of General Medical Sciences, National Institutes of Health     

Binding ofβ-adrenoceptor blocking drugs to human serum albumin,to α1-acid glycoprotein and to human serum

Summary The binding of 8 -adrenergic blocking drugs to human serum albumin, to ₁-acid glycoprotein and to serum from normal volunteers and from patients with rheumatoid arthritis was studied. Protein binding was determined in vitro using equilibrium dialysis of labelled drug at 25° C. Oxprenolol and propranolol were highly bound to serum, alprenolol, pindolol and timolol to a lesser degree, and atenolol, metoprolol and sotalol were negligibly bound. For the five compounds which were appreciably bound, the mean binding was significantly higher in serum from patients with rheumatoid arthritis than in serum from normal volunteers. For those drugs, binding to ₁-acid glycoprotein was higher than to human serum albumin, and binding to a mixture of both proteins approached that to serum from healthy volunteers. For each of these drugs there was a strong correlation between the serum ₁-glycoprotein concentration and the percentage binding.     

High-affinity 3H-imipramine binding in platelets from untreated and treated depressed patients compared to healthy volunteers

Specific high-affinity binding of ³H-imipramine to human platelets possesses very similar characteristics to the sites previously described in animal and human brains. In a study comparing the binding of ³H-imipramine in platelets obtained from 39 control volunteers with 37 hospitalized, untreated, severely depressed patients, the maximal binding of ³H-imipramine was found to be significantly lower in the depressed population. There were no differences in the K_D values. After 7–15 days of treatment with tricyclic antidepressant drugs, there was an improvement in the degree of the depression but no significant change in the maximal ³H-imipramine binding. After an average of 50 days treatment, Hamilton ratings had returned to normal, but the ³H-imipramine binding values remained unchanged.     

High affinity binding of3H-paroxetine and3H-imipramine to rat neuronal membranes

Paroxetine is the most potent and one of the most specific serotonin uptake inhibitors. High-affinity³H-paroxetine and³H-imipramine binding was compared in rat neuronal membranes. TheK _d value for³H-paroxetine binding to neuronal membranes was 0.08 nM, which is exactly the same value as with platelet membranes. TheK _d value for³H-imipramine binding to neuronal membranes was about 4 nM, which is higher than theK _d value for³H-imipramine binding to platelet membranes (0.5 nM). The results indicated that the³H-paroxetine binding site is identical in neuronal membranes and in platelet membranes; this binding site is probably located on the serotonin transport mechanism. In addition, part of the highaffinity³H-imipramine binding to neuronal membranes is probably located on the serotonin transport mechanism, but another part is located elsewhere. Furthermore the polypeptides containing the³H-imipramine binding sites may not be identical in neuronal and platelet membranes.     

Output of14CO2 in breath after oral administration of (14C-methyl) aminopyrine in hepatitis,cirrhosis and hepatic bilharziasis: Its relationship to aminopyrine pharmacokinetics

Summary The time-course of aminopyrine in plasma and of¹⁴CO₂ in breath was determined for 6 hours after oral administration of (¹⁴C-methyl) aminopyrine to healthy controls and to patients with hepatitis and hepatic fibrosis, cirrhosis and hepatic bilharziasis.¹⁴CO₂ in breath declined about 1.8 times more slowly than aminopyrine plasma levels, which suggests the occurrence of metabolite demethylation. This was confirmed by the slow elimination of¹⁴C from plasma, the formation of¹⁴CO₂ after aminopyrine had disappeared and the presence of a considerable amount of monomethyl-aminopyrine in plasma. The mean¹⁴CO₂ concentration in breath was correlated with but was not proportional to aminopyrine clearance, which was attributed to individual differences in aminopyrine half-life. Both a correlation and proportionality were found when¹⁴CO₂ extrapolated to zero time was used as a parameter of¹⁴CO₂ production. Hepatic disease affected aminopyrine clearance to a variable extent. In the hepatitis and fibrosis group, aminopyrine clearance was affected in 2 out of five subjects. In all except one cirrhotic subject aminopyrine clearance was markedly decreased. Moreover, in three out of seven cases aminopyrine absorption was impaired, presumably due to decreased gastrointestinal blood-flow. This may produce an erroneously low¹⁴CO₂ concentration in breath during the first two hours after aminopyrine administration. Hepatic bilharziasis was accompanied by very low aminopyrine clearance in all four cases. In two patients high apparent V_d values were observed, probably due to first-pass metabolism. Patients with ascites had V_d values within normal limits.     

Binding of piroxicam to synovial fluid and plasma proteins in patients with rheumatoid arthritis

Summary The protein binding of piroxicam in synovial fluid and plasma from patients with rheumatoid arthritis was studied in vitro by equilibrium dialysis. The binding parameters were calculated from the experimental data with the Scatchard model, assuming binding to two classes of sites. Each plasma sample was diluted to an albumin concentration equal to that of synovial fluid from the same patient. The association constants for primary and secondary binding sites in the concentration range of piroxicam 4.5–90·10^–5 mol/l were similar in synovial fluid and in plasma. For synovial fluid K₁=2.38·10⁵ l/mol and K₂=2.29·10³ l/mol; for plasma K₁=1.93·10⁵ l/mol and K₂=2.08·10³ l/mol. The number of binding sites was also the same in the two fluids. Although the concentration of piroxicam in synovial fluid was about half that in plasma, the binding of piroxicam to protein in synovial fluid was the same as in plasma.     

3H-Imipramine binding and serotonin uptake in platelets from untreated depressed patients and control volunteers

Human platelets possess specific high-affinity binding sites for ³H-imipramine which have similar characteristics to the sites previously described in human and animal brain. In a group of untreated depressed patients, the B_max of ³H-imipramine binding and the V _max of serotonin uptake in their platelets were found to be significantly lower than in a group of control volunteers. There was no significant difference in the K _d values for ³H-imipramine binding but the K _m values of ³H-serotonin uptake were decreased in the depressed patients. When the measurements of ³H-imipramine binding and ³H-serotonin uptake were compared in the same individual, however, there was no correlation between the individual B _max and V _max values or the K _d and K _m values. These results suggest that although the ³H-imipramine binding site and the mechanism for serotonin uptake are associated, they are not identical.     

In vitro and in vivo down-regulation of human plateletα 2-adrenoceptors by clonidine

Summary The effect of clonidine on the number of ₂-adrenoceptors in human platelet membranes, determined by³H-yohimbine binding, was investigatedin vitro andin vivo. Incubation of platelet membranes with clonidine (1–100 µM) for 16 h at 25 °C led to a concentration-dependent decrease in the number of³H-yohimbine binding sites of 10–25%; the affinity of³H-yohimbine to the sites was not changed (K_D approximately 3–4 nM). In such desensitized membranes, inhibition of³H-yohimbine binding by clonidine resulted in steep, monophasic displacement curves, which in comparison to the curves from control membranes (IC₅₀ for clonidine 90 nM), were shifted to the right (IC₅₀: 321 nM) and were not affected by 10^–4M guanosine-5-triphosphate (GTP).Treatment of 3 hypertensive patients with clonidine (3×150 µg/d for 7 days) reduced blood pressure and heart rate. Simultaneously, both³H-yohimbine binding sites on platelet membranes and plasma catecholamine levels decreased within three days and remained at a reduced level during treatment. After abrupt cessation of clonidine treatment, blood pressure, heart rate and plasma catecholamines rapidly increased, reaching values after two days similar to or higher than those before treatment.³H-yohimbine binding sites, however, initially decreased further before returning to control values. In platelet membranes derived from hypertensive patients treated with clonidine for at least three weeks, GTP (10^–4M) had no influence on inhibition of³H-yohimbine binding by (—)-adrenaline and clonidine. It is concluded that clonidine desensitizes ₂-adrenoceptors in human platelet membranesin vitro andin vivo. An important step in the desensitization process is the uncoupling of receptor occupancy by agonists and adenylate cyclase activity, as indicated by loss of the regulatory activity of GTP on desensitized membranes. The clonidine withdrawal syndrome may be caused by enhanced release of endogenous catecholamines not adequately regulated by presynaptic ₂-adrenoceptors, which have become subsensitive after chronic clonidine treatment.     

Pethidine binding to blood cells and plasma proteins in old and young subjects

Summary The distribution of³H-pethidine in whole blood was compared in old (63–86 years;n=11) and young (19–25 years,n=12) subjects using equilibrium dialysis. The plasma protein binding was 52.7±3.3% (mean ± SD) in the old subjects and 51.8±3.1% in the young; the difference was not statistically significant. Studies on isolated plasma protein fractions showed that the main pethidine-binding protein was ₁-acid glycoprotein. Accordingly, the degree of pethidine binding is likely to be affected by inflammatory disease rather than by age. The distribution of pethidine to blood cells showed no age-related difference; the ratio between whole blood and plasma concentrations was 0.99 in old and 0.98 in young subjects. In whole blood from old and young subjects, 43% and 41% of pethidine was present in erythrocytes, 27% and 26% in plasma water whereas 30% and 29% was bound to plasma proteins. The mean ratio between pethidine in cells and plasma water (2.01) indicates binding of the drug in or on the blood cells. These in vitro results do not support the previous theory that a decrease in intracellular pethidine distribution in old age was the reason for the reported higher plasma levels. A slower elimination rate remains the most likely explanation for the increased plasma concentration of pethidine in old patients.     

The effect of propranolol on exercise induced tachycardia is determined by plasma concentration and the density of adrenergic receptors on leukocytes

Summary The chronotropic response to a single oral dose of propranolol in 23 healthy subjects has been related to the plasma propranolol concentration and the density of -adrenoceptors on peripheral polymorphonuclear leucocytes. The percentage reduction in exercise-induced tachycardia was significantly correlated with the log plasma propranolol concentration within subjects but not between subjects. Taking the concentration of the active metabolite 4-hydroxypropranolol into account did not improve the interindividual correlation. The reduction in exercise-induced tachycardia was significantly correlated with the maximum binding density of (¹²⁵I)-hydroxybenzylpindolol on polymorphonuclear leucocyte membrane fragments measured before medication. A response index (% reduction in exercise-induced tachycardia/plasma propranolol concentration) was correlated with the maximum binding density of (¹²⁵I)-hydroxybenzylpindolol (predrug) at 2 h (r_s=0.72), 4 h (r_s=0.84) and 6 h (r_s=0.73) after dosing. The data suggest that interindividual variation in the response to propranolol after a single oral dose is determined by interindividual differences both in plasma propranolol and adrenoceptor density.     

Prolactin plasma levels and D2-dopamine receptor occupancy measured with IBZM-SPECT

By the application of¹²³([¹²³I]IBZM), an iodine-labelled dopamine D₂-receptor antagonist, brain D₂ receptors in humans can be visualized with single photon emission computed tomography (SPECT). The ratio of IBZM binding to striatal regions versus binding to frontal cortex (ST/FC ratio) provided a semiquantitative measurement of D₂ receptor binding in the striatum. This study investigated the relationship between receptor occupancy and plasma prolactin levels in 12 male patients treated with haloperidol, benperidol or clozapine. Prolactin levels were positively correlated with D₂ receptor occupancy, reflecting at least in part a comparable dopamine receptor antagonism in different dopaminergic pathways.     

Serum kinetics,bioavailability and bone scanning of 99mTc-labelled sodium olpadronate in patients with different rates of bone turnover

The activity of olpadronate labelled with technetium-99m(^99mTc) was monitored in plasma and urine samples after single oral (925 MBq ^99mTc/10 mg, coadministered with 50 mg cold drug) and intravenous (925 MBq ^99mTc/5 mg) administrations to two groups of patients with different rates of bone turnover. The first group comprised high bone turnover (HBTO) patients suffering from Paget's bone disease; the second group comprised patients with normal to low bone turnover (NBTO) having the diagnosis of rheumatoid arthritis and secondary osteoporosis. Kinetic variables were correlated with anthropomorphometric variables, biological markers of bone metabolism and plasma proteins. Data were also obtained after repeatedly dosing the HBTO patients. Additionally, Paget's bone and healthy bone (PB/HB) uptake before and after low-dose oral treatment were assessed by means of scintigraphy. Results showed that most of the kinetic variables did not differ between the two groups of patients, except for a greater V _ss and smaller blood area under the curve AUC in the patients with HBTO. After a repeated-dose administration period, the blood AUC activity and Whole Body Retention (WBR) of the HBTO patients tended to be similar to those of the NBTO patients. In both groups, after oral dosing, the C _max was 20 times lower than the C _0.5 after i.v. injection, and the oral bioavailability ranged from 3% to 4%. Finally, the plasma t _1/2 ranged from 9 to 14 h. Correlation coefficients were obtained from multiple regression analysis; kinetic variables showed very low correlations with anthropomorphometric measurements. In contrast the V _ss and WBR were significantly correlated with serum alkaline phosphatase levels and the V _ss also with urine hydroxyproline levels. Plasma protein concentration was also correlated with excretion parameters such as CL_P and plasma t _1/2 after an oral dose. Scintigraphic studies in the HBTO group allowed bone selectivity to be seen through skeletal drug uptake. The 15 Pagetic lesions analysed in the HBTO group showed a decrease in PB/HB ratio from 3.8 in the basal study to 2.7 after olpadronate administration for 30 days at the rate of 50 mg/day. In conclusion, the kinetic profile of ^99mTc-labelled olpadronate, mainly AUC and WBR, showed a dependence upon bone metabolism and seemed unrelated to body size variables. HBTO patients showed a lower blood AUC but a higher V _ss. Both variables may have been reflecting the fact that the drug binds selectively with calcified tissues and, in turn, with the target compartment. Scintigraphy confirmed the labelled-compound bone selectivity as a desirable feature for a bone-scanning agent.     

Sodium naproxen: concentration and effect on inflammatory response mediators in human rheumatoid synovial fluid

Twelve patients suffering from rheumatoid arthritis and having swollen knees were treated with 1.1 g/day of sodium naproxen administered in one dose, daily for 5 days.The 72-h wash-out period was verified by the absence of any nonsteroidal anti-inflammatory drug using a HPLC screening. Blood and synovial fluid samples were drawn just before treatment and 24 h after the last dose.Eicosanoids (PGE₂, 6-keto-PGF₁, TXB₂, LTB₄, LTC₄) in synovial fluid were determined by immunoenzy-matic assays. In plasma and synovial fluid, hyaluronic acid was assayed by radiometric assay and sodium naproxen by HPLC. Free drug was determined by equilibrium dialysis. Statistical analysis used nonparametric tests.Pain relief (evaluated on a visual scale), morning stiffness, and scores on the Lee and Ritchie indices all decreased significantly, as did PGE₂ and LTB₄ concentrations. The decrease in 6-keto-PGF₁ and TXB₂ was not significant. No significant change was found for LTC₄ and hyaluronic acid.Total concentrations of sodium naproxen were equivalent in plasma (16.1 g·ml^–1) and synovial fluid (18.9 g·ml^–1). Free fractions were significantly higher in synovial fluid (0.14%) than in plasma (0.11 %), as shown by binding of the drug to human serum albumin, at various protein concentrations.Interestingly, the clinical efficacy, as shown by decreases in morning stiffness and in the Lee index score, correlated with the free concentration of naproxen in synovial fluid.     

Mono- and divalent cations modulate the affinities of brain D1 and D2 receptors for dopamine by a mechanism independent of receptor coupling to guanyl nucleotide binding proteins

Summary In order to clarify the question of whether the modulatory effects of cations on dopamine receptor affinities are brought about by shifts in the equilibrium of receptor — G-protein — coupling, it was investigated whether mono- and divalent cations were still able to modulate rat striatal D1 and D2 receptor affinities after selective inactivation of the G-proteins linked to the two receptors. The G_S-protein coupled to the D1 receptor was eliminated by mild thermal inactivation, and the G_i- (or G_o-) protein associated with the D2 receptor by alkylation with a low concentration of N-ethyl-maleimide. Incubation of striatal membranes at 60°C completely abolished the specific binding of³H-GTP. Both treatments resulted in an increase of the IC₅₀-values for dopamine as a displacer of³H-SCH 23390 from D1- and of³H-spiperone from D2 receptors. Concomitantly, the formerly shallow D1 displacement curves became steeper, with their Hill coefficients increasing. This effect was less evident at D2 receptors. Guanosine triphosphate (GTP), which increased the IC₅₀'s of dopamine for both receptors approximately two-fold in control membranes, was without effect in pretreated samples, indicating an effective inactivation of the G-proteins. Na⁺ ions were still able to lower, and Ca²⁺ ions to increase the affinities of D1 and D2 receptors for dopamine after such inactivation of the respective G-proteins. It is concluded that the mechanism underlying the regulation of dopamine receptor affinities by mono- and divalent cations is independent of and superimposed upon the coupling of these receptors to guanyl nucleotide binding proteins.Abbreviations ANOVA Analysis of variance; G-proteins, guanyl nucleotide binding proteins (G_s: stimulatory, G_i: inhibitory); - GTP guanosine-5-triphosphate; Gpp(NH)p, 5-guanylylimidodiphos-phate; - NEM N-ethyl-maleimide     

Protein binding of 2-chloro 2′-deoxyadenosine (cladribine) in healthy subjects and in patients with leukaemia

The plasma protein binding of 2-chloro-2-deoxyadenosine (CdA) at 37°;C was studied by ultrafiltration in 5 healthy volunteers, in 11 patients with haematological malignancies and in purified protein preparations. In the patients, the binding of CdA to plasma proteins was 25.0% and in healthy subjects it was 21.1%. In a solution of human serum albumin (40 g·1^–1), 24.3% CdA was bound, but less than 5% was bound in a solution of ₁-acid-glycoprotein (0.7 g·1^–1). No dependence of binding on the concentration of CdA was found within a range 25–1000 nmol·1^–1.In conclusion, due to its limited binding to plasma proteins, any change in the binding of CdA is unlikely to have a major influence on its pharmacological effect.     

Plasma protein binding of the enantiomers of hydroxychloroquine and metabolites

Summary The in vitro binding of the enantiomers of hydroxychloroquine and its three major metabolites in pooled plasma obtained from four healthy volunteers and the binding of the enantiomers of hydroxychloroquine to purified plasma proteins has been investigated.The plasma protein binding of hydroxychloroquine was found to be stereoselective. The (S)-enantiomer of hydroxychloroquine was 64% bound in plasma, while (R)-hydroxychloroquine was 37% bound. Fifty % of (S)-hydroxychloroquine was bound to a 40 g·l^–1 solution of human serum albumin, while only 29% of the (R)-enantiomer was bound. The enantioselectivity of hydroxychloroquine binding was reversed in a 0.7 g·l^–1 solution of ₁-acid glycoprotein with (R)-hydroxychloroquine being bound to a greater extent than its optical antipode (41% versus 29%). The enantiomers of the metabolites of hydroxychloroquine were bound to a similar extent to plasma and purified plasma proteins.Binding of hydroxychloroquine to plasma and purified proteins was found to be linear over the racemic concentration range of 50 to 1000 ng·ml^–1 and hydroxychloroquine metabolite binding to plasma was linear over the range 25 to 500 ng·ml^–1.     

Reduced Insulin Sensitivity Is Related to Less Endogenous Dopamine at D2/3 Receptors in the Ventral Striatum of Healthy Nonobese Humans

Background:

Food addiction is a debated topic in neuroscience. Evidence suggests diabetes is related to reduced basal dopamine levels in the nucleus accumbens, similar to persons with drug addiction. It is unknown whether insulin sensitivity is related to endogenous dopamine levels in the ventral striatum of humans. We examined this using the agonist dopamine D_2/3 receptor radiotracer [¹¹C]-(+)-PHNO and an acute dopamine depletion challenge. In a separate sample of healthy persons, we examined whether dopamine depletion could alter insulin sensitivity.

Methods:

Insulin sensitivity was estimated for each subject from fasting plasma glucose and insulin using the Homeostasis Model Assessment II. Eleven healthy nonobese and nondiabetic persons (3 female) provided a baseline [¹¹C]-(+)-PHNO scan, 9 of which provided a scan under dopamine depletion, allowing estimates of endogenous dopamine at dopamine D_2/3 receptor. Dopamine depletion was achieved via alpha-methyl-para-tyrosine (64mg/kg, P.O.). In 25 healthy persons (9 female), fasting plasma and glucose was acquired before and after dopamine depletion.

Results:

Endogenous dopamine at ventral striatum dopamine D_2/3 receptor was positively correlated with insulin sensitivity (r(7)=.84, P=.005) and negatively correlated with insulin levels (r(7)=-.85, P=.004). Glucose levels were not correlated with endogenous dopamine at ventral striatum dopamine D_2/3 receptor (r(7)=-.49, P=.18). Consistently, acute dopamine depletion in healthy persons significantly decreased insulin sensitivity (t(24)=2.82, P=.01), increased insulin levels (t(24)=-2.62, P=.01), and did not change glucose levels (t(24)=-0.93, P=.36).

Conclusion:

In healthy individuals, diminished insulin sensitivity is related to less endogenous dopamine at dopamine D_2/3 receptor in the ventral striatum. Moreover, acute dopamine depletion reduces insulin sensitivity. These findings may have important implications for neuropsychiatric populations with metabolic abnormalities.     

Die Wirkung von Cyclohexylamin auf die Noradrenalinaufnahme und den Noradrenalingehalt des Rattenherzens

Summary Cyclohexyalmine is considered as an indirectly acting sympathomimetic amine that can be generated by the metabolic conversion of the non-nutritive sweetener cyclamate. Sprague-Dawley rats were injected intraperitoneally with increasing doses of Cyclohexylamine. The concentration of Cyclohexylamine in the plasma was determined by means of gas-liquid-chromatography and correlated with the uptake of³H-dl-norepinephrine in the heart. Cyclohexylamine caused a dose-dependent inhibition of the uptake of³H-norephinephrine (50% inhibition by 59.0 mg/kg) and decreased the concentration of endogenous norepinephrine.The plasma half life time of Cyclohexylamine was 75.3 min. Following a dose of 40 mg/kg, the inhibition of norepinephrine uptake lasted about 2 h. 50% inhibition was obtained at a plasma concentration of 24.8 g/ml of Cyclohexylamine corresponding to 2.5×10^–4 M. These findings are consistent with Cyclohexylamine being an indirectly acting sympathomimetic amine which is some orders of magnitude less potent than related substances.

Frl. Brigitte Allmeling danken wir für die Mithilfe bei den Versuchen.     

Pharmacokinetics and protein binding of cefazolin in morbidly obese patients

Purpose

The aim of this study was to assess the pharmacokinetics and protein binding of cefazolin in morbidly obese patients undergoing bariatric surgery, to study the influence of bodyweight measures and age on pharmacokinetic parameters and to evaluate unbound cefazolin concentrations over time in this population.

Methods

Twenty morbidly obese patients (bodyweight 112?C260?kg, body mass index 38?C79?kg?m^?2) were studied following the administration of cefazolin 2 g at induction of anaesthesia. Blood samples were collected up to 4 h post-dosing to determine total and unbound plasma cefazolin concentrations. Non-compartmental pharmacokinetic data analysis was performed.

Results

Cefazolin clearance was 4.2 ± 1.0 L?h^?1 (mean ± standard deviation) and showed a negative correlation with age (p?=?0.003) but not with bodyweight measures (p?>?0.05). Volume of distribution was 13.0 ± 3.1 L and correlated positively with bodyweight measures (p????0.001). Saturable protein binding was observed with a median protein binding of 79% (interquartile range 74?C82), which proved similar to reported protein binding in non-obese patients. In all patients, unbound cefazolin concentrations remained above 1?mg?L^?1 (minimal inhibitory concentration for 90% (MIC₉₀) of methicillin-sensitive isolates of Staphylococcus aureus in Europe) until 4 h post-dosing.

Conclusions

Younger age??and not bodyweight??was significantly associated with higher cefazolin clearance. However, as in all patients with bodyweights up to 260?kg, unbound plasma cefazolin concentrations remained above 1?mg?L^?1 until 4 h after the intravenous administration of a 2-g dose. As such, re-dosing within 4 h or dosing with another antibiotic class should only be considered in the case of a higher MIC₉₀ of the local isolates.