Don W. Shoeman

Pharmacokinetics of drugs in patients with the nephrotic syndrome.

Since the binding of drugs to plasma proteins can significantly after the intensity of pharmacological and toxicological effects of drugs, we studied the pharmacokinetics of three drugs in patients with hypoalbuminemia secondary to the nephrotic syndrome, but with relatively normal renal function. No significant differences were seen in the pharmacokinetic parameters observed for antipyrine, a drug which is less than 10% bound to plasms proteins. The percentage of unbound diphenylhydantoin, a highly plasms protein-bound drug, was found in patients with the nephrotic syndrome to be twice that of healthy individuals (19,2 vs. 10.1%, P smaller than 0.001). However, there was also a lower steady-state plasma concentration of diphenylhydantoin (2.9 plus or minus 0.6 vs. 6.8 plus or minus 0.6 mug/ml, P smaller than 0.001) secondary to an increase in the plasms clearance (0.048 plus or minus 0.019 vs. 0.022 plus or minus 0.006 liter/kg.h, P smaller than 0.001) in the nephrotic patients. The net effect is no difference in the absolute concentration of unbound diphenylhydantoin in healthy individuals (0.69 plus or minus 0.05 mug/ml) and patients with the nephrotic syndrome (0.59 plus or minus 0.06 mug/ml). Qualitatively, similar differences were observed with clofibrate. The dose of these drugs need not be routinely reduced in patients with the nephrotic syndrome as long as they have reasonably normal renal function (creatinine clearance greater than 50 ml/min). With all highly bound acidic drugs, knowledge of the concentration of unbound drug is essential to the proper interpretation of total blood levels and subsequent treatment of the patient.

The Alteration of Plasma Proteins in Uremia as Reflected in their Ability to Bind Digitoxin and Diphenylhydantoin

Digitoxin was 86% bound to plasma from uremic patients while plasma from healthy volunteers bound 90%. The binding of diphenylhydantoin (DPH) was also depressed in uremia. We isolated albumin by curta

Correlation of the plasma elimination of antipyrine and the appearance of 4-hydroxy antipyrine in the urine of man.

A new gas chromatographic method for the determination of antipyrine and 4-hydroxy antipyrine in biological fluids is described. Utilizing these methods, we find a significant correlation (r = 0.89, P < 0.001) between the plasma elimination half-life of antipyrine and the rate of appearance of 4-hydroxy antipyrine conjugate in the urine. This observation validates previous studies utilizing the rate of plasma decay of antipyrine as a measure of drug metabolism in man.

Effect of in vivo Elevation of Free Fatty Acids on Protein Binding of Drugs

Warfarin and diphenylhydantoin (DPH) were displaced from plasma proteins in rats by in vivo elevation of free fatty acids (FFA) produced by exercise or by i.p. injection of d,l-epin

The effect of spironolactone on antipyrine metabolism in man.

Spironolactone treatment was associated with a decrease in the plasma antipyrine half-life in all 9 volunteers studied. This was associated with an increased excretion of 4-OH antipyrine but not 3-hydroxymethyl antipyrine in their urine. The plasma antipyrine disappearance rate correlated with the excretion rate of 4-OH antipyrine in the urine. Spironolactone increased the excretion of 6-βOH cortisol in the urine. These data provided indirect evidence that spironolactone is an inducer of hepatic drug hydroxylation in man.

Biliary excretion of lead in rats rabbits, and dogs☆

Abstract The disappearance of 210 Pb from the blood and plasma of rats and its excretion into bile was measured for 2 hr after the iv administration of 0.1, 0.3, 1.0, 3.0, or 10 mg/kg of inorganic lead. The maximal rate of excretion of lead into the bile was approximately 1.0 μg/min/kg after the 3 higher doses. The concentration of lead in the bile was found to be 40–100 times that in the plasma for the 3 lower doses. This was due largely to the higher concentration of lead in the liver than in the plasma (10- to 35-fold higher) and partially to the higher concentration in the bile than in the liver (3- to 4-fold higher). Essentially none of the lead in the bile, plasma, and liver was dialyzable. Lead exhibited a 5-fold greater affinity for liver than bile and a 3-fold greater affinity for liver than plasma. The mitochondrial fraction contained the highest concentration of lead. Changing the rectal temperature of rats altered the biliary excretion of lead markedly; when the temperature was increased from 30 to 40°C, the biliary excretion of lead increased 20-fold. Marked species differences in the biliary excretion of lead were observed. Rabbits excreted lead into the bile at a rate less than one-half, and dogs excreted lead at a rate less than one-fiftieth, that observed in the rat. The results indicate that lead is excreted into the bile of rats against an apparent concentration gradient and that an apparent transport maximum exists. This suggests that the liver may have an active transport mechanism for the excretion of metals.

High-presure liquid chromatographic assay of theophylline in biological fluids

Abstract A method has been developed to determine the level of theophylline in biological fluids. The sample is acidified and then extracted with a mixture of chloroform and isopropanol containing oxaxepam as an internal standard. The methylxanthines are separated by high-pressure liquid chromatography using oxypropionitrile on a Porasil C column packing and quantitated in the effluent by UV absorption. This technique avoids special treatment of the plasma to eliminate caffeine and analyze the materials at temperatures at which they are stable. The method is rapid, specific and precise.

Diphenylhydantoin: correlation between protein binding and albumin concentration.

ZusammenfassungEs besteht eine negative Korrelation zwischen dem nichtgebundenen Anteil an Diphenylhydantoin und der Albuminkonzentration im Plasma des Patienten. Aus dieser Relation kann die Eiweißbindung ohne spezielle Bindungsstudien graphisch bestimmt werden. Die Ergebnisse hierzu wurden aus einer Untersuchung erhalten, in der bei Patienten mit nephrotischem Syndrom ein auf das Doppelte erhöhter Anteil an nichtgebundenem Diphenylhydantoin beobachtet wurde. Eine Dosisreduktion war bei diesen Patienten jedoch nicht erforderlich, da die absolute Konzentration des nichtgebundenen Medikamentes als Folge einer Erhöhung des Verteilungsvolumens und der Plasma-Clearance nicht erhöht war.SummaryThe unbound fraction of diphenylhydantoin is inversely correlated with the patients serum albumin concentration and can be accurately estimated graphically without binding analyses. The data for this relationship was obtained from a study in which we observed that the unbound fraction of diphenylhydantoin was two times higher in patients with the nephrotic syndrome. However, in these patients it was not necessary to diminish the dosage since the absolute concentration of unbound drug was unchanged due to a compensatory increase in the apparent volume of distribution and plasma clearance.

Toxicity of a hepatotoxic laxative preparation in tissue culture and excretion in bile in man

Dioctyl sodium sulfosuccinate (DSS), 100 or 200 mg., was given orally to patients with indwelling T‐tube biliary drainage. Concentrations of the drug in bile measured by gas chromatography ranged from 4 to 9 × 10−5M. Before recent modifications, DSS and oxyphenisatin were the components of a laxative preparation, Dialose Plus. The cytotoxic potential of both drugs on human liver cell cultures (Chang) was quantitated by loss of lactate dehydrogenase and ß‐glucuronidase into surrounding tissue culture media after exposure to concentrations of the drugs between 10−6M and 2 × 10−4M for 4 to 24 hours. At 4 hours and higher concentrations, only DSS or the 2 drugs together were cytotoxic; at 24 hours high concentrations of oxyphenisatin became cytotoxic. At most other lower concentrations the addition of the 2 drugs to the same cultures resulted in greater cytotoxicity than either did separately. These data suggest that clinical hepatotoxicity might be facilitated when patients achieve “critical” concentrations of one or both of these drugs in liver parenchyma.

Placental transfer of diphenylhydantoin in the goat.

Abstract Constant blood levels of diphenylhydantoin (DPH) were maintained in pregnant goats by an intravenous infusion. Venous blood was sampled simultaneously from the conscious, unanesthetized mother and fetus during the infusion. Maternal serum levels of DPH were maintained at 14·8 mean, 0·82 S.E. μg/ml. At equilibration, the corresponding fetal level of DPH was 7·6 (0·44 S.E.) μg/ml. When the maternal and fetal sera were equilibrated against each other for 18 hr in vitro , the corresponding levels were found to be 13·2 mean, 1·9 S.E. and 6·9 mean, 1·6 S.E. μg/ml respectively. Differences in plasma protein concentration and binding affinity account for the observed maternal-fetal distribution of DPH. Maternal plasma binds more DPH than fetal plasma even when diluted to the same protein concentration as fetal plasma. Antipyrine, which is not appreciably bound to plasma protein at the concentrations studied, distributes equally between maternal and fetal plasma in vivo .