Low Volume Of Distribution Research Articles

Liposomal formulations of cyclosporin A: influence of lipid type and dose on pharmacokinetics.

Liposomal formulations of Cyclosporin A (CyA)3 have been described in more than 30 publications to substitute Cremophor EL (CrEL), a triricinoleate ester of ethoxylated glycerol, as drug carrier. However, conflicting reports did not allow to draw consistent conclusions about the influence of liposomes on CyA pharmacokinetics (PK) and pharmacodynamics. A series of liposomal CyA-formulations with varying liposome composition and lipid dose but constant CyA dose was compared in rats. Data were analysed with a PK-model taking into account the varying volume of distribution with the varying lipid concentration in blood. Surface properties and lipid type of liposomes are not important PK predictors of liposomal CyA, at least for small dosages of liposomes. Rather, the absolute lipid amount and the lipophilicity of cyclosporins are critical factors influencing the PK of liposomal CyA. The higher the concentration of lipid in blood and the greater the lipophilicity of cyclosporin is, the higher are the concentrations of CyA in blood. These relations may explain the inconsistent literature results. Together with earlier observations from our group the above findings indicate, that CyA is not caged in the liposomal membranes. Reports in literature, which claim lower clearance and a lower volume of distribution of CyA in obese rats compared to lean rats, support our assumption about the involved mechanisms. A semi-quantitative model of CyA distribution is presented, which points to the variable free fraction of CyA in plasma as the crucial factor for all previously reported phenomena in liposomal CyA formulations.

ETHANOL ELIMINATION IN ALCOHOL-TREATED PREGNANT RATS

The effects of chronic intake of alcohol on ethanol elimination were studied in 20-day pregnant rats, in their foetuses, and in virgin rats. Experimental animals received ethanol in drinking water (from 10% to 25% in 2 months) (alcohol group), whereas controls drank only water. At the end of chronic exposure, alcohol dehydrogenase activity was determined in stomach and liver and cytochrome P-450 was measured in liver. In a complementary assay, the same experimental groups of rats were given an acute dose of ethanol (2 g/kg body wt, 25% w/v) either intragastrically or intraperitoneally, at the end of the chronic exposure, to determine first-pass ethanol metabolism and pharmacokinetic parameters of its elimination. Significant differences were found between alcohol and control groups for liver and stomach alcohol dehydrogenase activity in pregnant rats. Only in virgins did chronic alcohol treatment significantly increase the liver cytochrome P-450 content. In virgin rats, the first-pass metabolism of ethanol was lower in the alcohol group than in control. By contrast, in control rats, the first-pass of ethanol was lower in pregnant, than in virgin, rats. The metabolic rate of ethanol elimination (mg/kg body wt/hr) was clearly enhanced in alcoholic virgin rats, demonstrating that this model of chronic alcoholism induces metabolic tolerance to ethanol. In alcoholic pregnant rats, a surprisingly low theoretical volume of body ethanol distribution (55 ml/100 g body wt vs. 80 ml/100 g body wt in the other groups) masked their metabolic tolerance to ethanol. This preliminary study should be taken into account when evaluating the effects of chronic or/and acute alcohol intake during pregnancy on the circulating ethanol levels in foetuses and on future development of the foetal alcohol syndrome.

Pharmacokinetics of Oxicam Nonsteroidal Anti-Inflammatory Agents

Oxicam nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of structurally closely related substances with anti-inflammatory, analgesic and antipyretic activities. They have a weakly acidic character and are extensively bound to plasma proteins. Piroxicam, the most widely used oxicam, is well absorbed after oral administration. Peak plasma concentrations (Cmax) of the drug are reached within 2 to 4 hours. Piroxicam has a small volume of distribution and a low plasma clearance. It undergoes hepatic metabolism and only 5 to 10% is excreted unchanged in urine. The elimination half-life varies between 30 and 70 hours. Age of the patient and renal or hepatic dysfunction do not seem to have any major effect on the pharmacokinetics of piroxicam. The drug reduces the renal excretion of lithium to a clinically significant extent, but the clinical significance of piroxicam-aspirin (acetylsalicylic-acid) and piroxicam-acenocoumarol interaction has not been established. Ampiroxicam, droxicam and pivoxicam are prodrugs of piroxicam that have been synthesised to reduce piroxicam-related gastrointestinal irritation. All prodrugs are well absorbed, but Cmax values are reached later than those following administration of piroxicam. Tenoxicam is used in the management of rheumatic and inflammatory diseases. Mean Cmax values are achieved 2 hours postdose. Food reduces the rate but not the extent of absorption. The oral bioavailability of tenoxicam is 100% and rectal bioavailability is 80%. Like piroxicam, tenoxicam has a low volume of distribution and low plasma clearance. It is eliminated through hepatic metabolism. The mean elimination half-life is 60 to 75 hours. The pharmacokinetics of tenoxicam are independent of patient age, or concurrent liver or renal diseases. High doses of aspirin have been shown to increase the elimination of tenoxicam, but this has little clinical significance. Isoxicam was in widespread clinical use until its worldwide marketing was suspended because of fatal skin reactions. Isoxicam is completely absorbed, but Cmax values are not reached until 10 hours postdose. It has a low plasma clearance, approximately 5 ml/min (0.3 L/h), and low volume of distribution. The mean elimination half-life is 30 hours and does not appear to be affected by the age of the patient. Isoxicam potentiated the anticoagulant effect of warfarin, necessitating a 20% dosage reduction. Lornoxicam differs from other oxicam NSAIDs because it has a short elimination half-life of 3 to 4 hours. On the basis of limited data, some individuals seem to eliminate lornoxicam very slowly, suggesting the presence of polymorphic metabolism. The pharmacokinetics of cinnoxicam and sudoxicam have not been studied thoroughly.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetics of Ketoprofen After Intravenous and Intramuscular Administrations to Rabbits

AbstractThe pharmacokinetics of ketoprofen was studied in rabbits following intravenous and intramuscular administrations of ketoprofen, both at a dose of 4.0 mg.Kg-1. Plasma levels of ketoprofen, as a function of time, were determined by a reversed-phase high performance liquid chromatography. The disposition of ketoprofen was described by a two-compartment open model with elimination from the central compartment. A model-independent method using the statistical moment theory was also applied. Pharmacokinetics of ketoprofen was characterized as a drug with terminal half-life of 3.15 hr, low apparent volumes of distribution (V = 0.031 L.Kg-1, Vdss = 0.070 L.Kg-1 and Vdβ = 0.130 L.Kgc-1). The mean residence time (MRT) was found to be 1.44 hr for i.v. injection and 2.86 hr for i.m. injection. The clearance (CL) and apparent volume of distribution at steady state (Vdss) after i.v. injection was determined to be 0.027 L.Kg-1.hr-1 and 0.03 9 L.Kg-1, respectively. The absorption rate constant from the limb musc...

Pharmacokinetics of benzydamine after intravenous, oral, and topical doses to human subjects

The pharmacokinetics of the anti-inflammatory drug benzydamine were determined after intravenous infusion of 5 mg to six healthy male subjects. Benzydamine was characterized as a drug of relatively low systemic clearance (ca. 160 ml min-1) but high volume of distribution (ca. 1101); the apparent terminal half-life in plasma was ca. 8 h. Benzydamine was well absorbed after oral administration, as indicated by a mean systemic availability of 87 per cent. However, absorption of the drug was low (less than 10 per cent of the dose) after its use by male subjects as a mouthwash, or after its application to female subjects as dermal cream and vaginal douche preparations. The data suggest that benzydamine is generally not well absorbed through the skin and non-specialized mucosae, thereby limiting unrequired systemic exposure to this drug when it is used by these routes.

Gas chromatographic determination of butoxyacetic acid in human blood after exposure to 2-butoxyethanol

Venous blood samples from five male volunteers exposed to 20 ppm 2-butoxyethanol (BE) for 2 h were collected at 0, 2, 4, and 6 h from the start of exposure and analyzed by gas chromatography after simultaneous ion-pair extraction and derivatization with pentafluorobenzyl bromide. Butoxyacetic acid (BAA), a major metabolite of BE, was found in all samples except those collected prior to exposure. This is the first time to our knowledge that the analysis of BAA in human blood has been reported. Concentrations of BAA in blood ranged from 22 to 60 microM. These concentrations were about two orders of magnitude lower than those causing swelling and hemolysis of human erythrocytes in vitro. The BAA blood level peaked after 2-4 h. The decrease between 4 and 6 h indicates an average half-time of BAA in blood of about 4 h, which is in accordance with previously observed half-times in urine. The low renal clearance of BAA (22-39 ml/min) indicates extensive binding to blood proteins and poor tubular secretion of the substance. Binding of BAA to blood components is also indicated by the low apparent volume of distribution of approximately 15l.

Pharmacokinetics of Pyridostigmine in Dogs

The pharmacokinetics of the cholinesterase inhibitor pyridostigmine has been studied in six male Beagle dogs after iv infusion and after oral doses as an immediate-release syrup and as an extendedrelease tablet, all at a level of ~0.6 mg/kg. Pyridostigmine was characterized as a drug of relatively long terminal half-life (8.3 h ± 2.1 SD), low systemic clearance (13 mL/min/kg ± 1 SD) and high volumes of distribution (Vdλz, 8.7 L/kg ± 1.9 SD and Vdss, 3.9 L/kg ± 0.9 SD). The ratio of mean residence times in tissues and plasma was >4, indicating a high affinity of peripheral tissues for the drug. This ratio was about twofold higher in three of the dogs than in the others. Pyridostigmine was slowly and incompletely bioavailable in these dogs; the systemic availability was 44.4% ± 4.3 SD from the syrup and 33.6% ± 9.5 SD from the tablet. Pyridostigmine disposition in these dogs was largely determined by distribution processes.

Drug Therapy in Patients Undergoing Continuous Ambulatory Peritoneal Dialysis

Continuous ambulatory peritoneal dialysis (CAPD) is an accepted alternative to haemodialysis in the treatment of end-stage renal failure. The frequently used intraperitoneal administration of antibiotics to treat peritonitis and the possible role of CAPD in the elimination of drugs has stimulated pharmacokinetic research in this field. The 2 principal results derived from these studies are: (1) the elimination capacity of CAPD for drugs given systemically or orally is very low, and (2) drugs administered intraperitoneally rapidly enter the circulation, a significant amount of drug being absorbed from the peritoneal cavity. This pharmacokinetic behavior is easily understood considering some basic and simple pharmacokinetic principles: the higher the volume of distribution of a substance, the lower will be the percentage of drug present in the peritoneal cavity. Thus, a prerequisite for rapid drug elimination by CAPD is a low body volume of distribution of a particular drug. Only in such a case will the drug diffuse into the peritoneal space to a significant extent. For dosing regimens in CAPD patients, the fraction of the dose eliminated by the peritoneal route should be known or estimated. This fraction depends on the relation of the peritoneal clearance to the total body clearance, and on the protein binding of the drug. The low flow rate of the peritoneal effluent (approximately 10 L/day = 7 ml/min) appears to be the most important limiting factor for the low extraction capacity of CAPD. The list of drugs that have been found to be significantly eliminated by CAPD is short: particular mention should be made of the aminoglycosides and some cephalosporins. The data on the peritoneal elimination of vancomycin are inconsistent. Although the intravenous and oral routes have been successfully used for the treatment of peritonitis, the time course of antibiotic concentrations in the peritoneal space appears to favour the peritoneal route of drug administration. During peritonitis, intraperitoneally administered drugs enter the circulation more rapidly and completely, due to the increased permeability of the peritoneal membrane. As long as the dialysate outflow rate and protein binding of the drug are not extensively altered by peritoneal inflammation, however, the extraction capacity of CAPD appears to remain low.

Glycopyrrolate: pharmacokinetics and some pharmacodynamic findings.

In the present study, a sensitive and reproducible radioreceptor assay (RRA) was used to evaluate the basic pharmacokinetic properties of glycopyrrolate, a quaternary amine with peripheral antimuscarinic activity. Based on the plasma levels after a single intravenous injection, 6 micrograms/kg (n = 6), the distribution phase half-life (2.22 +/- 1.26 s.d. min) and the elimination phase half-life (0.83 +/- 0.29 h) of glycopyrrolate were short due to the low distribution volume during the elimination phase (0.64 +/- 0.29 l/kg) and to the respectively high total plasma clearance value (0.54 +/- 0.14 l/kg/h). An intramuscular injection, 8 micrograms/kg (n = 6), was followed by a fast and predictable systemic drug absorption and clinical effects (heart rate increase, dry mouth). In this group the time to maximum plasma concentration (tmax) was 27.48 +/- 6.12 min and the maximum plasma concentration (Cmax) was 3.47 +/- 1.48 micrograms/l. After oral drug intake, 4 mg (n = 6), an apparently low and variable gastrointestinal absorption was found (tmax = 300.0 +/- 197.2 min, Cmax = 0.76 +/- 0.35 microgram/l), thus indicating that the oral route of drug administration is of no value as a routine premedication. The correlation between the plasma concentration of glycopyrrolate and the drug effects appears to be variable. Because of its sensitivity, the RRA method proved to be quite useful in evaluating the kinetics of glycopyrrolate and its relationship to various clinical effects.

Distribution of RU 486 and its demethylated metabolites in humans.

The concentrations of RU 486 and its demethylated metabolites were determined by RIA in samples of myometrium, abdominal adipose tissue, and serum, which were collected at hysterectomies performed 12-15 h after oral administration of 200 mg RU 486. The RU 486 concentrations in myometrium were similar in the five women studied, with a mean of 148 +/- 58 (+/- SD) ng/g (344 +/- 135 pmol/g). The adipose tissue RU 486 levels varied more, the mean concentration being 447 +/- 191 ng/g (1041 +/- 445 pmol/g). The serum RU 486 concentrations ranged from 175-899 ng/ml [mean, 396 +/- 259 ng/mL (922 +/- 603 nmol/L)]. In these women the nonprotein-bound fraction of [6,7-3H]RU 486 varied from 1.4-3.1% (mean, 2.3%). The approximate concentrations of the combined mono- and didemethylated metabolites of RU 486 were 1.4, 3.1, and 5.2 times higher in adipose tissue, myometrial tissue, and serum, respectively, than those of the parent RU 486. In vitro, rapid and nonsaturable accumulation of [6,7-3H]RU 486 from phosphate buffer into adipose tissue was inhibited by the addition of alpha 1-acid glycoprotein, the specific serum transport protein for RU 486, to the buffer medium. Accumulation of [6,7-3H]RU 486 in myometrial specimens was poor. The enterohepatic cycling of RU 486 was assessed in four normal subjects by repetitive intake of charcoal subsequent to ingestion of 200 mg RU 486. Compared to other normal subjects, the serum levels and areas under the concentration curves were lower and t1/2 values shorter in the group given charcoal, suggesting that in vivo RU 486 may be partly pooled in the enterohepatic cycle. Our studies suggest that despite the low volume of distribution and the effective serum binding of RU 486, the myometrial and adipose tissue concentrations of RU 486 and its metabolites were similar (approximately 10(-9)-10(-10) mol/g) after oral intake of RU 486.

Kinetic investigations into the possible cause of low serum histidine in rheumatoid arthritis.

To investigate the cause of low serum histidine in rheumatoid arthritis (RA) single oral and intravenous doses of L-histidine were administered to patients with active RA, and to an equal number of age and sex matched control subjects. In the first study 13 patients and their controls received a 100 mg kg-1 dose of L-histidine as an aqueous slurry. Significant differences were seen in body weight, predose baseline serum histidine concentration, Cmax, t1/2, and area under curve, AUC0-infinity. In a second study six patients and six controls each received a 50 mg kg-1 dose of L-histidine both orally and intravenously on two separate occasions. The patients with RA had a lower baseline serum histidine concentration, a lower volume of distribution, and a shorter plasma half life than the controls, but these differences were not statistically significant. No difference was seen in bioavailability or clearance. Low serum histidine in RA is unlikely to be due to malabsorption from the gut, uptake by abnormal gut flora, or increased metabolism.

Cetirizine, a Novel Antihistamine

Cetirizine, an oxidative metabolite of hydroxyzine, is a cyclizine class H1-receptor antagonist with diminished CNS activity currently under investigation. It has a novel pharmacokinetic profile with a 9-hour half-life, lower volume of distribution and total body clearance, minimal metabolism and essentially renal excretion. Minimal binding to CNS receptors has been demonstrated in animal models. In contrast to its parent compound and diphenhydramine, cetirizine has an effect comparable to placebo on psychomotor function and multiple sleep latency tests. Inhibition of histamine-induced bronchospasm and mild bronchodilation has also been demonstrated. U.S. and European clinical trials have affirmed its safety and efficacy in histamine-associated disorders.

Determination of the enantiomers of indoprofen in blood plasma by high-performance liquid chromatography after rapid derivatization by means of ethyl chloroformate

A rapid method for the determination of (+)- and (−)-indoprofen in blood plasma has been developed and applied to pharmacokinetic work. By means of ethyl chloroformate, indoprofen is coupled to leucinamide, a reaction which is complete in less than 3 min at room temperature. The diastereoisomeric derivatives are then separated by reversed-phase high-performance liquid chromatography. In two surgical patients given racemic indoprofen intravenously, the pharmacologically active (+)-enantiomer had a lower clearance and a lower distribution volume than the (−)-enantiomer, which gave it a slightly longer half-life.

Pharmacokinetics of the stable prostacyclin analogue, nileprost, in the rat

The synthesis of radioactive nileprost, tritium-labelled at positions 18 and 19, and its application to the pharmacokinetics and biotransformation of this chemically stable prostacyclin derivative in the rat is described. 3H-Nileprost was absorbed after oral administration with a half-life of 23 min reaching maximum concentrations in the plasma 90 min after treatment. After intravenous injection there was a threephasic decline in plasma levels with half-lives of 15 min, 0.9 h and 11 h, respectively. Unchanged drug was eliminated with t= 14 min. Brain levels of drug or metabolites were less than 5 % of corresponding plasma concentrations. In autoradiographs after i.v. and oral administration a very low volume of distribution was found with maximum levels in the liver, the kidney and the stomach mucosa. Nileprost was very rapidly excreted, mainly by biliary elimination. Ten metabolites were detected in urine and bile, one of them being formed exclusively in the gut wall. The main fraction of H-activity in urine and bile, however, was due to unchanged drug.

Differences in the plasma kinetics of daunorubicin in normal and leukemic rats.

The plasma pharmacokinetics of the anthracycline drug daunorubicin in doses of 1 and 10 mg/kg body weight were compared in normal and leukemic inbred Sutton-August rats (50-70 x 10(9) leukemic cells/1 blood). The area under the plasma concentration versus time curve was about 25 times larger in the leukemic rats at both dose levels. The data indicate that daunorubicin has a lower volume of distribution in leukemic rats as compared with normals. The large reduction in plasma clearance of daunorubicin in the leukemic rats can to some extent be explained by impairment of hepatic and renal functions but the results indicate that the leukemic state per se was of importance for the observed pharmacokinetic differences. This finding may be of importance for the treatment of patients with a high leukemic cell load, since higher retention of the drug in the central compartment leads to lower concentrations in poorly vascularized tissues, which favours the development of resistant leukemic cell clones.

Simultaneous determination of furosemide and two of its possible metabolites in biological fluids.

By the means of thin-layer chromatography (TLC) prior to fluorometry it was possible to determine furosemide (F) in plasma and urine with improved specificity. Antranilic acid (A) and 4-chlor-5-sulphamoyl-antranilic acid (CSA) could be determined simultaneously with F in plasma. In urine, only F and A could be determined quantitatively by this method. The sensitivity is 0.1 microgram/ml for F and 0.15-0.20 microgram/ml for A and CSA. By means of TLC prior to fluorometry the blank value for F was reduced in normal subjects and in different groups of patients, and its diurnal variation was eliminated. The average values of the plasma concentrations of F after the intravenous injection of 40 mg into 12 normal subjects were at all times found to be lower by the TLC method than by the fluorometric method without TLC. A higher plasma clearance and a lower volume of distribution were found for F when the values obtained by the TLC method were used for the calculation.

Pentobarbital elimination in patients with poor renal function.

Drug oxidation is slowed in experimental uremia in animals but has been reported to be normal or accelerated in uremic patients. Eleven normal subjects and 9 uremic patients were each given 100 mg pantobarbital orally. Several blood samples were drawn over a 36-hr period starting on the morning after the dose. Plasma pentobarbital concentration was measured by GLC. The log concentration values were graphed against time elapsed after dose for each patient, and the plasma T/2 and extrapolated value of concentration at the time of drug administration (Co) were determined. The T/2 values in normals ranged from 18 to 48 hr; mean, 26.5 +/- 9.2 (SD). In uremic patients, T/2 values are 10 to 38 hr, mean, 21.3 +/- 8.7. Four of the uremic patients had T/2 values below 18 hr (which was the lowest in the normals). The apparent volumes of distribution of pentobarbital (aVD = dose divided by Co) were 62 +/- 25 L in the normal subjects and 58 +/- 24 L in the uremic patients. The four uremic patients with the short T/2 values tended to have small apparent volumes of distribution so that the metabolic clearnce rates (aVd X 0.693 divided by half-life) were normal in 3 of them. We conclude that pentobarbital elimination is normal in renal failure. Some uremic patients have short plasma T/2 values for pentobarbital, and these more likely result from low apparent volumes of distribution with normal metabolic clearance rates than from accelerated metabolism of pentobarbital.

Intrarenal blood flow distribution in canine puppies.

Extract: The present study was designed to examine the developmental changes in renal blood flow distribution in canine puppies utilizing the techniques of xenon-133 (133Xe) washout, anatomic measurements, and para-aminohippuric acid (PAH) clearances and extractions. The distribution patterns determined by analysis of the xenon washout curves were confirmed by studies of the intrarenal distribution of injected radioactive microspheres. The mean total blood flow was 1.2 ml/g kidney/min at 6 weeks of age and rose progressively to the adult value of 3.5 ml/g kidney/min at 14–16 weeks of age. The mean Component I flow, 1.7 ml/g/min at 6 weeks, increased to 4.7 ml/g/min at 14–16 weeks of age. The increase in Component I flow was associated with an increase in PAH extraction ratio. The low renal blood flow observed in the puppy less than 6 weeks of age appears to be due in large part to a small cortical volume. Anatomically, the amount of cortex/medulla ratio was less in the puppy than in the adult, and this was supported by the relatively low cortical volume of distribution noted in the washout studies. At 10 and 12 weeks of age, when the relative cortical mass approximated that found in the adult, the Component I flow rate was still low, but from age 12 weeks, Component I flow and total renal blood flow increased markedly. Renal blood flow increased during a period when cardiac output per kilogram body weight was constant and total peripheral resistance was rising. The progressive age-dependent increase that was noted in total renal blood flow was primarily due to an increase in cortical flow. The increased cortical flow was in part a consequence of cortical growth; change in sympathetic tone may also have contributed.