Change In Volume Of Distribution Research Articles

Limitations of clearance determination using the single sample distribution volume method. An error analysis on the basis of compartment models.

To investigate the error possibly contained in the single sample distribution volume method for the determination of renal clearance, a mathematical model was applied to describe the effect of changes in distribution volume, clearance, intravascular space, intracompartmental exchange and the time point of blood sampling. The method was found to be valid only under well-defined circumstances (Topt = 45 +/- 5 min, Cl = 390 +/- 50 ml/min, Vd = 16.7 +/- 4 l, alpha = 0.05.V1 ml/min, V1/Vd = 0.5 +/- 0.05) as shown in sample calculations. Two-compartment model-based error calculations demonstrate that this technique implies at best an uncertainty of +/- 10% or more. Whilst it can be used preferably in healthy, normal-weight adults, it is not applicable, without error, under all other circumstances.

The Effect of Diltiazem on Hepatic Drug Oxidation Assessed by Antipyrine and Trimethadione

The effect of pretreatment for 3 days with diltiazem 60 mg three times a day on the pharmacokinetics of 500-mg antipyrine and 250-mg trimethadione was studied in six healthy male subjects. Diltiazem decreased the total body clearance from 34.0 +/- 8.0 to 28.6 +/- 6.1 mL/min (P less than .01), and prolonged the elimination half-life from 12.6 +/- 3.0 to 14.3 +/- 2.5 hours (P less than .01) of antipyrine without any changes in volume of distribution. The cumulative renal excretion (% dose) of antipyrine was significantly increased from 2.23 +/- 0.73 to 2.78 +/- 0.83% (P less than .05). Clearances of production for three major antipyrine metabolites, norantipyrine (4.31 +/- 1.64 to 3.50 +/- 1.28 mL/min, P less than .01), 3-hydroxymethylantipyrine (4.67 +/- 1.63 to 3.82 +/- 1.34 mL/min, P less than .01) and 4-hydroxyantipyrine (10.47 +/- 3.41 to 8.16 +/- 2.82 mL/min, P less than .01) were reduced significantly by diltiazem. On the other hand, diltiazem did not produce any significant changes in pharmacokinetic parameters of trimethadione and plasma concentration ratio, oxidative major metabolite of trimethadione to trimethadione itself. These results suggest that other drugs metabolizing the same hepatic oxidative pathways as antipyrine, may be influenced by diltiazem.

Pharmacokinetics of opioid agonists and antagonists

A major reason for clinical variations between opioids is differences in their physicochemical and pharmacokinetic properties. Important factors are p K a , lipid solubility and protein binding. Opioids are basic drugs that, with the exception of alfentanil, have p K a values greater than 7.4, so that the ionized form of the drug predominates in the blood. The p K a of alfentanil is 6.5 so that 90% of alfentanil is non-ionized at pH 7.4. This facilitates its access into the CNS. p K a is also an important determinant of absorption from the gastrointestinal tract. Opioid pharmacokinetics are also affected by changes in blood and tissue pH (e.g. during respiratory alkalosis). While morphine is mainly bound to albumin, the most important binding protein for the fentanyl analogues is α 1 -acid glycoprotein (AAG). Change in the concentration of this protein can affect opioid pharmacodynamics, and has special relevance during pregnancy and in the newborn. Because of immaturity of the cytochrome P-450 isoenzyme system, neonates metabolize opioids much less efficiently than older children or adults. Generally the pharmacokinetics of an opioid are similar in children and in young adults, although often clearance is greater in young children. In elderly patients the influence of age on opioid pharmacokinetics is less well defined and many of the clinical differences between young and elderly patients in their responses to opioids may be due to pharmacodynamic differences or attributable to concomitant diseases or medication. The pharmacokinetics of these drugs are also influenced by renal and hepatic disease, although the extent is very drug dependent. The elimination of morphine metabolites is especially affected by decreases in renal filtration. Not surprisingly, cardiac surgery with cardiopulmonary bypass markedly affects opioid pharmacokinetics. Apart from changes in distribution volume and hepatic clearance, sequestration of opioids on to the extracorporeal circuit may be important for some opioids. Significant uptake of opioids by the lungs has also been demonstrated.

Decreased Systemic Clearance of Lorazepam in Humans With Spinal Cord Injury

Serum concentration-time course profiles, serum protein binding, and disposition parameters of lorazepam (LRZ), a benzodiazepine with sedative-hypnotic, anxiolytic, and anti-seizure properties, were studied as part of a systematic effort to define population-specific pharmacokinetic behavior in humans with chronic spinal cord injury (SCI). Twenty-four healthy subjects (nine tetraplegic, six paraplegic, nine able-bodied) were given an IV bolus of 2.0 mg of LRZ. Noncompartmental estimation of pharmacokinetic parameters disclosed a 37% decrease in the total systemic clearance (CL) of LRZ in tetraplegic patients. Altered LRZ clearance was observed independently of significant changes in volume of distribution or serum protein binding. The early elimination of LRZ (0-10 hr) was characterized by wide fluctuations in serum concentration suggestive of impaired enterohepatic circulation and could be distinguished from LRZ elimination observed in able-bodied subjects. We conclude that decreased systemic CL and the altered terminal elimination profile of LRZ are attributable to the pathophysiology of SCI.

The effect of malaria infection on paracetamol disposition in the rat

The effect of Plasmodium berghei infection, a rodent malarial model, on the dispostion of paracetamol (50mg/kg, i.v.) was investigated in rats. Malaria infection (MI) resulted in a significant decrease in clearance (control: 21.6 ± 5.5 vs test: 11.8 ± 2.9 mL/min/kg, P < 0.005) with no change in volume of distribution and a significant prolongation of the elimination half-life (control: 30.7 ± 6.3 vs 53.3 ± 12.1 min, P < 0.005) of paracetamol in malaria infected rats. These changes were not related to the severity of MI. Malaria infection also decreased biliary clearance of paracetamol (64%) but not its glucuronide and sulphate conjugates in the bile compared with controls. In addition, glutathione conjugates were not detected in bile samples of malaria infected rats. These data suggest that important pathways of drug detoxification may be compromised by MI in a relatively selective fashion and the relevance of these findings to the clinical use of drugs eliminated by these pathways merits further study.

Effects of Posture and Sleep on the Pharmacokinetics of Paracetamol (Acetaminophen) and Its Metabolites

The effects of posture and sleep on the pharmacokinetics of paracetamol (acetaminophen) 500 mg and its metabolites were studied in 8 healthy men. The mean residence times for paracetamol or its metabolites were significantly altered by change in posture or by sleep, whereas other pharmacokinetic parameters were unchanged. The change in mean residence time is consistent with a faster absorption of paracetamol during ambulation. The present data suggest that the proposed posture-related changes in volume of distribution do not exist, and that there is no pharmacokinetic basis for a headache being relieved by taking paracetamol and lying down.

4‐Hydroxyanisole: Human Pharmacokinetics

The pharmacokinetic behaviour of 4-hydroxyanisole (4HA) has been studied in ten female patients with recurrent malignant melanoma confined to the lower limb. Ten grams of 4HA was infused twice each day via a catheter placed in the common femoral artery for a maximum of 4 days. Blood samples were collected after the first and fourth infusions in all patients and the serum 4HA concentration assayed. Following infusion, the serum 4HA concentration declined in two phases, the half-lives (t1/2) of the distribution and elimination phases being 6.3 and 70.9 min, respectively. The serum 4HA concentrations and area under the curve (AUC) declined significantly between the first and fourth infusions. There was a significant rise in the apparent volume of distribution (VD) of 4HA between these times but no change in the t1/2 of the elimination phase or the clearance rate. It is concluded that there is no evidence that enzyme induction influences the clearance of 4-hydroxyanisole from the bloodstream in the short-term. However, it may be appropriate to adjust dosage regimens to take account of the change in VD that occurs with time.

Effect of nifedipine on antipyrine and theophylline disposition

On the basis of reports that some calcium channel blockers impair the elimination of some drugs, the effect of nifedipine on the disposition of antipyrine and theophylline was assessed in healthy volunteers. Antipyrine half-life of 10.04 +/- 1.43 h (mean +/- SD) after a week intake of nifedipine (20 mg twice daily) was not significantly different from the control value of 10.64 +/- 2.15 h; nor was that of 10.02 +/- 1.49 h after 2 weeks pretreatment with the calcium channel blocker in eight healthy volunteers. Control antipyrine clearance (ml min-1) of 44.40 +/- 10.58 was not significantly different from that of 45.66 +/- 9.34 and 46.87 +/- 9.63 after nifedipine pretreatment of 1 and 2 weeks, respectively. Similarly volume of distribution was unaltered: 0.601 +/- 0.074, 0.591 +/- 0.078 and 0.602 +/- 0.051 l kg-1, respectively. A week pretreatment with nifedipine did not significantly alter either of theophylline half-life (7.32 +/- 0.81 h (control) to 7.50 +/- 0.80 h) or clearance (42.10 +/- 5.84 ml min-1 (control) to 43.77 +/- 4.00 ml min-1) in six volunteers. However the change in volume of distribution: 0.451 +/- 0.053 l kg-1 (control) to 0.483 +/- 0.062 l kg-1 was significant (p less than 0.025). Generally, theophylline plasma levels were lower after nifedipine pretreatment and the difference was significant at 2 and 4 h post-dosing (p less than 0.05). It is suggested that nifedipine, unlike diltiazem and verapamil, is unlikely to interfere with the functional integrity of the hepatic mixed-function oxygenase enzymes, but might displace theophylline from plasma protein.

Gastric contents alter blood alcohol levels and clearance after parenteral ethanol

Several different substances, including water, charcoal, fructose, montmorillonite clay, and liquid diets used for chronic ethanol exposure, were given intragastrically to rats, followed by a low dose of ethanol injected subcutaneously. Peak blood alcohol levels (BAL) and ethanol clearance rates were found to differ depending upon the type of gastric contents. As expected, fructose lowered peak BAL and increased ethanol clearance, and charcoal lowered peak BAL, but decreased ethanol clearance. Two liquid diets, Shorey and Sustacal, when compared to an intragastric water load, also lowered peak BAL and increased ethanol clearance of subcutaneously-administered ethanol. The difference between intragastric water and Shorey liquid diet was also seen when ethanol was administered intravenously, suggesting that absorption of ethanol from the subcutaneous site was not being affected. When sleep-inducing doses of ethanol were given subcutaneously, intragastric substances did not produce differences in sleeptimes. In in vitro studies, only charcoal was able to bind ethanol, presumably by absorption onto charcoal particles. Volume of distribution measurements were inversely related to the peak BALs measured at 60 minutes after injection, suggesting that ethanol was partitioning between the blood and stomach contents. We conclude that the presence in the stomach of various substances can lower peak BAL and increase ethanol clearance in a rapid fashion, primarily through a change in volume of distribution and possibly through a rapid change in stomach or liver metabolism of ethanol.

Attenuation of rifampicin-induced theophylline metabolism by diltiazem/rifampicin coadministration in healthy volunteers.

On the basis of reports that diltiazem binds to the hepatic microsomal enzymes and inhibits the metabolism of coadministered drugs, we investigated the effect of a 240 mg daily dose of the calcium channel blocker for a week on theophylline metabolism in 8 healthy male volunteers aged 20-24 years and weighing 56-68 kg. None of theophylline half-life (9.7 h), volume of distribution (0.514 l.kg-1) and total clearance (0.63 ml.min-1.kg-1) after pretreatment differed from the respective control value of 9.5 h, 0.519 l.kg-1 and 0.65 ml.min-1.kg-1. In 6 of the volunteers, 600-mg daily dose of rifampicin for a week induced theophylline metabolism. The control half-life of the bronchodilator (9.6 h) was reduced to 5.5 h and its total clearance (0.64 ml.min-1.kg-1) increased to 1.22 ml.min-1.kg-1. There was no change in volume of distribution. In these 6 volunteers, intake of diltiazem (240 mg daily), concurrently with rifampicin for a week, significantly elevated theophylline half-life to 6.2 h as well as reduced its clearance to 1.03 ml.min-1.kg-1. The volume of distribution did not change. Furthermore, diltiazem-induced absolute fall in theophylline clearance correlated significantly with its post-rifampicin value (r = 0.895). It is suggested that diltiazem has no effect on theophylline metabolism in non-induced subjects. However, rifampicin-induced metabolism of the bronchodilator could be attenuated by diltiazem when the two drugs are given concurrently.

Effects of coadministration of propafenone on the pharmacokinetics of digoxin in healthy volunteer subjects.

Previous reports have suggested an interaction between propafenone and digoxin. We investigated the pharmacokinetics of IV digoxin when given alone (Phase I), after pretreatment with propafenone 150 mg every 8 hours for seven days (Phase II), and after propafenone 300 mg every 8 hours for 7 days (Phase III). The total body clearance of digoxin during Phase I was 2.45 ml/min/kg and was 2.17 ml/min/kg during Phase II (NS) and decreased to 1.92 ml/min/kg during Phase III (P less than 0.05). The renal clearance and half-life of digoxin were not significantly altered by propafenone. There was a trend towards a decrease in the volume of distribution of digoxin from 9.43 L/kg in Phase I, to 9.33 L/kg in Phase II, and 8.02 L/kg in Phase III. Similarly there was a trend towards a decreased nonrenal clearance of digoxin from 1.21 ml/min/kg during Phase I to 1.01 ml/min/kg during Phase II and to 0.75 ml/min/kg during Phase III. The changes in volume of distribution and nonrenal clearance parallel each other resulting in no change in the elimination half-life of digoxin. It is postulated that the mechanism of this interaction is due to decreases in the volume of distribution and nonrenal elimination of digoxin by propafenone. The degree of this interaction was related to the dose of propafenone. The magnitude of this interaction may be greater in patients and, thus, may require a reduction in the digoxin dose.

Effect of two different types of malnutrition on the rate of elimination of ethanol in rats

Rats were fed “3% casein” or a “calorie deficient” diet, in the form of commercial pellet diet (SDS) at 50% of the amount consumed by the control group, which was fed SDS pellets ad libitum. Both of the deficient groups showed failure of weight gain in comparison with the control group. Blood levels of ethanol were measured for 3 hr after intraperitoneal injection of 1 or 1.5 g/kg at 15, 29 and 36 days after commencement of the diet. In addition the calorie deficient group was studied immediately after feeding as well as in the fasting state. Blood levels of ethanol were measured and the apparent volume of distribution and rate of removal of ethanol from the blood were calculated. A rate of ethanol metabolism/g of liver was derived. The rate of removal of ethanol was markedly decreased in the 3% casein group to less than half of control values. Three hours after injection of ethanol circulating levels were less than 50 mg 100 ml in the control and calorie deficient groups but over if 200 mg 100 ml in the group fed protein deficient diets. There were no major changes in volume of distribution and the only explanation for the finding is that there is a failure of ethanol metabolism in the rats fed the low protein diet. The implication is that protein deficient human populations who often consume considerable quantities of ethanol may have a high level of tissue exposure to ethanol though the rate of metabolite formation may be low.

Interindividual changes in volume of distribution of cefazolin in newborn infants and its prediction based on physiological pharmacokinetic concepts

The purpose of this study was to investigate factors affecting the volume of distribution of cefazolin (a β-lactam antibiotic) in newborn infants with bacterial infections, and to propose a method for predicting the volume of distribution at steady state per body weight (Vdss/BW). Cefazolin and tobramycin (an aminoglycoside) were simultaneously given to newborn infants (aged 2 to 28 d), and plasma concentration‐time data were analyzed on the basis of model-independent moment analysis. The Vdss/BW values ranged from 0.212 to 0.373 L/kg for cefazolin and from 0.384 to 0.541 L/kg for tobramycin. The unbound fraction of cefazolin in plasma (fp) fluctuated widely, from 0.22 to 0.83, among patients. The Vdss/BW value for cefazolin was characterized by both large extracellular water volume and a remarkable change in fp, and could be predicted as a function of fp using physiological pharmacokinetic concepts. Moreover, interindividual changes in the unconjugated bilirubin:albumin molar ratio were predominantly responsible for the individual variation in the fp values of cefazolin in newborn infants.

The effect of ciprofloxacin on antipyrine metabolism.

The effect of multiple-dose ciprofloxacin on antipyrine metabolism was studied in patients suffering from bacterial infections. The patients were given antipyrine 15 mg/kg intravenously before and after ciprofloxacin treatment. The dosage of ciprofloxacin was 500 mg bd by mouth for 8-10 days. Blood samples were taken at 0, 2, 4, 6, 10 h. Antipyrine total clearance was significantly decreased after ciprofloxacin treatment (0.85 +/- 0.45 vs. 0.52 +/- 0.24 ml/min/kg): elimination rate constants for antipyrine were decreased in all patients after ciprofloxacin, whereas no change in volume of distribution was observed. The average half-life of antipyrine was increased from 9.45 +/- 3.74 h to 14.92 +/- 3.32 h. In two males with advanced chronic hepatic failure the antipyrine half-lives were extremely prolonged. Our results support the hypothesis that ciprofloxacin inhibits intrinsic hepatic drug-metabolizing capacity and may be a source of clinically important drug interactions, particularly in patients with liver disease.

Pharmacokinetics and pharmacodynamics in critically ill patients.

AbstractThe rapidly changing physiology of critically ill patients causes variations in the absorption, distribution, metabolism, excretion, and pharmacodynamic effect of drugs used to treat these patients. Alterations in fluid status, cardiac, renal and hepatic function, and circulating serum proteins necessitate increased attention to drug selection and dosage modification. Cardiac failure results in decreased absorption, metabolism, and excretion of drugs while renal failure results in parent drug and metabolite accumulation, increases in unbound drug, and changes in distribution volume. The changes in hepatic blood flow and protein binding, and decreases in hepatocellular mass and enzyme function that occur in hepatic failure may alter the clearance of several drugs. Serum drug concentrations are helpful in defining the pharmacokinetics and ultimately the pharmacodynamic effect of the drugs used in critically ill patients. The serum drug concentrations must be interpreted in association with their pharmacodynamic effect and the clinical situation. Adjusting drug therapy based on pharmacokinetic principles is discussed in detail with specific suggestions for dosage modifications in renal and hepatic failure.

Age-dependent change in warfarin distribution volume in rats: effect of change in extracellular water volume.

The pharmacokinetics of insulin was studied following intravenous administration of 14C-inulin to 1-d, 1-, 3- and 8-week-old rats. The distribution volume of inulin varied 2-fold, from 689 ml/kg in 1-d-old rats to 340 ml/kg in 8-week-old rats in the growth process of rats. This result was similar to that of warfarin and there was a statistically significant correlation between the distribution volume of warfarin and inulin (r = 0.984, p less than 0.02). In the growth process of rats, the Kp values of warfarin in muscle, which play an important role in the distribution kinetics of warfarin changed in parallel with those of inulin. These results and pharmacokinetic considerations indicated that in warfarin, which is highly bound to serum protein and shows a small distribution volume, the change in the distribution volume in the growth process of rats following administration of a pharmacologically realistic dose (1 mg/kg) is led by the change in the extracellular volume of tissues and that the change in serum protein binding of warfarin might play a minor role in the change in the distribution volume in the growth process.

Kinetics of hexobarbital and dipyrone in critical care patients receiving high-dose pentobarbital.

The effect of pentobarbital treatment in a mean dose of 30 mg/kg/day on the clearance of hexobarbital (Evipan) and dipyrone (Novalgin) has been evaluated in critical care patients receiving a large number of drugs as comedication. Eleven patients treated with pentobarbital showed a hexobarbital half-life of 2.79 h and a total plasma clearance of 9.80 ml X min-1 X kg-1 as compared to 10 patients without pentobarbital administration in whom there was a significantly longer half life (6.92 h) and lower clearance (2.97 ml X min-1 X kg-1). The kinetics of hexobarbital were correlated with the urinary excretion of D-glucaric acid, a non-invasive parameter of drug metabolising activity. In 10 patients on pentobarbital, the total plasma clearance of N-4-methyl-aminoantipyrine, the active form of dipyrone, did not differ from that in 8 patients not receiving pentobarbital. As drug kinetics show great variability in these patients, it is difficult to discriminate enzyme induction from other mechanisms, for example competitive inhibition or changes in volume of distribution. In the presence of pentobarbital, however, induction of drug metabolising enzymes should be considered as a possible reason for the higher clearance of hexobarbital.

Dose-dependent pharmacokinetics of cimetidine in the rat.

The pharmacokinetics of cimetidine were studied in the rat after intraperitoneal administration of 10, 40 and 100 mg/kg. The area under the plasma concentration-time curve increased more than proportionately with dose. The total plasma clearance of cimetidine decreased as the dose increased (4.11 to 2.21 l/h per kg) with a consequent increase in half-life (24.0 to 37.9 min) but no change in volume of distribution (mean 2.31 l/kg). The fraction of dose excreted unchanged increased slightly with dose (0.37 to 0.45), whereas the fraction excreted as the sulphoxide metabolite decreased significantly with increased dose (0.35 to 0.14). Both the renal clearance (1.52 to 0.99 l/h per kg) and the formation clearance of the sulphoxide metabolite (1.45 to 0.30 l/h per kg) decreased with increasing dose. Residual clearance, calculated as the difference between total clearance and the sum of renal and metabolic clearance, did not change with dose (mean 1.08 l/h per kg). The formation clearance of the sulphoxide metabolite became saturated at a lower cimetidine concentration than the renal clearance.

Effect of a Moderate Blood Exchange with Fluosol-Da 20% on the Disposition of Digoxin in the Dog

AbstractThe effect of a perfluorochemical blood substitute (Fluosol-DA 20%) on the disposition kinetics of digoxin in the dog was studied. An intravenous dose of digoxin was administered at either 0.25 or 24 hours following a 30% blood exchange with the dog's own blood (SHAM group) or Fluosol-DA (treatment group). A significant change in the initial volume of distribution and mean residence time in the serum was noted when digoxin was administered 0.25 hours after the Fluosol-DA blood exchange. This volume of distribution change was not observed when digoxin was administered 24 hours after the Fluosol-DA blood exchange. No change in the t1/2, total body clearance, or volume of distribution at steady-state was observed in any of the treatments. No change in the partitioning of digoxin in the blood was noted following Fluosol-DA administration.

Pharmacokinetics of Terbutaline during Pregnancy

LYRENÄS, S.; GRAHNEN, A.; LINDBERG, B.; LINDSTRÖM, B.; LÖNNERHOLM, G. Author Information