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Results for “Plasma Protein Binding Capacity”

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At least 19 recordsLinked to original sources
PubMed1993

Apparent valproic acid neurotoxicity in a hypoalbuminemic patient.

OBJECTIVE: To report a case of possible neurotoxicity caused by markedly elevated free valproic acid (VPA) plasma concentrations. CASE SUMMARY: A patient with a history of a mixed-type seizure disorder that had been treated with oral VPA 1000 mg four times daily for the previous two years was admitted to the neurology service with the chief complaint of increasing difficulty in walking and involuntary muscle jerks that were new in onset. The patient was hypersomnolent and dysarthric. The total plasma VPA concentration was 103 micrograms/mL, which was only slightly above the recommended therapeutic range (50-100 micrograms/mL). VPA free fraction and free plasma concentrations, however, were unexpectedly elevated (26 percent, 26.8 micrograms/mL, respectively). Further laboratory evaluation revealed a serum albumin concentration of 33 g/L. The neurologic symptoms resolved upon VPA dosage reduction. DISCUSSION: VPA displays concentration-dependent protein binding, resulting in disproportionate increases in drug free fraction with increasing drug concentration. This effect may be magnified in patients with decreased plasma protein-binding capacity. The plasma protein-binding kinetics of VPA are reviewed and the implications for therapeutic drug monitoring are discussed. CONCLUSIONS: It is likely that the markedly elevated free VPA plasma concentrations contributed to the neurologic symptoms displayed in this patient. In patients with decreased albumin concentrations, failure to recognize concentration-dependent protein binding, as well as exclusive reliance upon total drug concentrations, may lead to erroneous pharmacokinetic and therapeutic interpretations.

Adult↗
PubMed1990

Flavone acetic acid and plasma protein binding.

Both the capacity of healthy human, cancer patient, and mouse plasma proteins to bind flavone acetic acid (FAA) and the qualitative differences in the plasma protein-binding site were studied. The binding capacity of plasma proteins for FAA was saturated within the therapeutic range in both species. The binding of FAA to plasma protein was significantly greater in both healthy human and cancer patient plasma than in mouse plasma. Plasma from patients with cancer bound on the average less FAA than did healthy patient plasma. The concentration of albumin in the plasma varied between healthy humans, cancer patients, and mice, being 5.3 +/- 0.7, 4.7 +/- 0.8, and 3.9 +/- 0.3 g/100 ml, respectively. The protein binding of FAA was found to be dependent on the plasma albumin concentration, but albumin concentration alone was not adequate for the accurate prediction of the percentage of FAA protein bound. Scatchard plots indicated that healthy human plasma had a greater number of high-affinity binding sites than did mouse plasma. FAA binds at the indolebenzodiazepine binding area on albumin and can be displaced from this site by salicylic acid and clofibric acid, but only at supratherapeutic concentrations. Our results indicate that alterations in plasma albumin could contribute to a variable effect with FAA. Therefore, the influence of serum albumin concentration and the nonlinearity of FAA protein binding should be considered in assessment of the appropriateness of a dose schedule for FAA.

Animals↗
PubMed2000

Mechanisms for the formation of protein-bound homocysteine in human plasma.

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. Greater than 70% of homocysteine in circulation is protein-bound. An in vitro model system using human plasma has been developed to study mechanisms of protein-bound homocysteine formation and establish the equilibrium binding capacities of plasma for homocysteine. Addition of homocysteine to plasma caused an initial rapid displacement of cysteine and a subsequent increase in protein-bound homocysteine. This rapid reaction was followed by a slower oxygen-dependent reaction forming additional protein-bound homocysteine. To determine the equilibrium binding capacity of plasma proteins for homocysteine, plasma was treated with 0.5-10 mM dl-homocysteine for 4 h at 37 degrees C under aerobic conditions. Under these conditions the equilibrium binding capacity was 4.88 +/- 0.51 and 4.74 +/- 0.68 micromol/g protein for male (n = 10) and female (n = 10) donors, respectively. The mechanism of protein-bound homocysteine formation involves both thiol-disulfide exchange and thiol oxidation reactions. We conclude that plasma proteins have a high capacity for binding homocysteine in vitro.

Blood Proteins↗
PubMed2000

Human hepatic metabolism of a novel 2-carboxyindole glycine antagonist for stroke: in vitro-in vivo correlations.

1. The hepatic metabolism of 3-[-2(phenylcarbamoyl) ethenyl]-4,6-dichloroindole-2-carboxylic acid (GV150526), a novel glycine antagonist for stroke, was investigated. 2. After a single intravenous administration of 800 mg GV150526 to healthy volunteers, six metabolites were observed. The major metabolites detected in human plasma have been shown by mass spectrometry to be glucoronides and one sulphate conjugate. 3. After incubation of GV150526 for 6 and 24 h with human liver slices, three glucuronide metabolites were observed. After incubation of GV150526 with pooled human liver microsomes, only one metabolite was observed, with the same molecular weight and HPLC retention time as the synthetic standard GV217053 (GV150526 hydroxylated on the para-position of the phenyl ring). 4. GV150526 hydroxylase enzyme kinetics--a step before sulphation--was determined using pooled human microsomes and was shown to be catalysed by cytochrome P4502C9. Glucuronidation kinetics towards GV150526 using microsomal preparations were also determined. Glucuronidation of GV150526 was observed with UGT1A1 cDNA-expressed protein, but not with UGT1A6. 5. The above enzyme kinetic data were used to calculate intrinsic clearance after scaling-up and hepatic clearance were calculated. Since GV150526 has a high plasma protein binding capacity, the effect of GV150526 binding to microsomal protein was determined. Thus, enzyme kinetic data were corrected, plotting the free (unbound) concentration of GV150526 versus enzymatic velocities: apparent Vmax did not alter significantly but apparent Km was approximately 10-fold lower. Correlation of these corrected enzyme kinetic data to predict clearance with in vivo clearance of GV150526 was good when both fu(plasma) and fu(microsomes) were included in the clearance calculations.

Adult↗
PubMed1985

[Tissue diffusion of flumequine into human renal and prostatic tissues. Assay of flumequine by high performance liquid chromatography after administration of 800 mg/day over 48 hours, the sampling being done 12 hours after the last ingestion].

Diffusion of flumequine into human renal and prostatic tissues was studied. Chemical characteristics and the natural antibacterial spectrum of the compound are described and its rapidity of absorbtion emphasized, blood levels being detected 30 minutes after administration. Maximum plasma levels were reached after 2 to 3 hours and were of the order of 17 mcg/ml, half-life being approximately 10 hours. Plasma protein binding capacity was 60 to 70%, indicating liposolubility enabling diffusion into prostatic parenchyma. Flumequine was recovered in the urine 2 hours after oral administration, maximum urinary concentrations being reached after between 3 and 6 hours, and being of the order of 280 mg/ml after single-dose 40 mg administration. The product was still recovered from the urine 12 hours later, and 60 to 70% of the dose administered after 24 hours, including 20.6% of active form. To evaluate renal and prostatic tissue diffusion 2 series of patients were studied 10 after renal surgery and 14 prostatic operations. Diffusion was excellent into renal parenchyma since the mean ratio between renal tissue and plasma concentrations was 2.41. Urine concentrations were even more extraordinary since the ratio was 136. In contrast, prostatic tissue concentrations were lower than plasma concentrations, the ratio between the two being 0.26, although levels is prostatic tissue were still sufficiently elevated to be effective against germs sensitive to flumequine.

Anti-Infective Agents, Urinary↗
PubMed2006

Prediction of cytochrome p450-mediated hepatic drug clearance in neonates, infants and children : how accurate are available scaling methods?

Correct dosing of drugs in neonates, infants and children is hampered by a general lack of knowledge about drug disposition in this population. Suggested methods to improve our knowledge without performing conventional full-scale investigations include population pharmacokinetic studies, allometric scaling of drug disposition according to bodyweight and in silico prediction of pharmacokinetics. The last method entails scaling of pharmacokinetic parameters according to age-dependent changes in drug absorption and elimination capacity, plasma protein binding and physiological characteristics of the subjects. Maturation (or ontogeny) of the drug-metabolising part of the cytochrome P450 (CYP) enzyme system is thus an important factor in the calculations for most drugs. The aim of this commentary is to test and critically examine the proposed methods to estimate hepatic clearance (CL) as a function of age (0-20 years), with CYP3A-mediated metabolism as the case in point. Midazolam and alfentanil were used as model drugs. Allometric scaling failed to predict the CL of midazolam and alfentanil in neonates. Calculations using in vitro findings on CYP maturation gave better estimates for neonates but very divergent ones for older infants and children. This was chiefly due to very different data on CYP3A4/5 ontogeny in three published studies. In the age range where full adult CYP activity per gram of liver could be assumed, allometric scaling and in silico predictions gave similar results. These predictions were also in approximate agreement with clinical data.The findings with the two model drugs can very probably be generalised to most drugs cleared by CYP-dependent hepatic metabolism. Allometric scaling accounts for development of body size and function but not for the fact that the drug-metabolising capacity of the liver is generally low at birth. The crucial question in the prediction of CL is thus when the activity of the applicable CYP isoform(s) attains adult levels. There are still not enough data on this, particularly when different studies even on the same CYP isoform have given very divergent results. It may also be pointed out that CYP ontogeny is an area where we have at least some information. There are several other important developmental changes about which we know practically nothing. Thus, while allometric scaling is generally unreliable for prediction in neonates and infants, the alternative method of in silico prediction can at present be used only to obtain tentative initial estimates of drug CL. Neither of the methods can be used as a substitute for actual clinical studies.

Aging↗