Change In Volume Of Distribution Research Articles

Ask the Experts

Q Is it appropriate to adjust body surface area (BSA) and intravenously administered vasoactive medication dosage against daily weight changes in the intensive care unit (ICU)? Because of these significant changes, is admission weight acceptable? Is there such a thing as “dry weight”? If so, how is it defined and measured?A Nancy Faulkner, RPh, BS, replies:BSA is not an appropriate parameter by which to calculate or modify inotropic and vasopressor drug infusion doses in the ICU. BSA is not a kinetic variable; it remains nearly constant regardless of changes in patient weight. Weight is a good kinetic variable for predicting drug concentration, dose, and therapeutic response. It better reflects changes in volume of distribution of the “size of the tank” into which drugs are distributed. Drug doses for the inotropic vasopressor agents, which have wide therapeutic ranges and short durations of action, should be calculated on body weight. BSA is generally reserved for dosing agents with narrow therapeutic indices, such as oncologic drugs.The significant question becomes whether to respond to changes in patient body weight when calculating doses. The controversy is an issue only for initial dosing. The drugs under consideration—dobutamine, dopamine, isoproterenol, phenylephrine, epinephrine and norepinephrine—are all short-acting medications that are titrated to achieve a desired pharmacologic response. Changes in weight because of fluid overload, dehydration, or organ system (cardiac, renal, pulmonary, hepatic) function may result in changes in volume of distribution of drugs accompanied by changes in clinical response. The infusion rate is adjusted according to standard guidelines, or nomograms, until the appropriate response is reestablished. When considering the initial rate of infusion for these compounds, determine the dosing weight by using the following considerations:\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \[Dosing\ weight=IBW\ [(ABW-IBW)\ {\times}\ 0.4]\] \end{document}A practical method is simply to split the difference between ABW and IBW. Patients who can be identified as having abnormal fluid weight on admission to the ICU should probably be dosed on actual body weight, because the volume of distribution is larger than normal at this point. Vasopressors will distribute into the fluid compartments and initial doses could be too low unless one accounts for this possibility.“Dry weight” is a parameter used in hemodialysis, where the maximum amount of weight (fluid) that can be removed is measured by blood pressure response. The lowest weight achieved before the patient becomes hypotensive is considered the dry weight. It is not of practical utility for drug dosing.A reference list supporting the contentions of this article is not available due to the paucity of research defining the “best” dosing weight for intravenous vasoactive drugs. The research question is not compelling because the safety and efficacy profiles of these compounds do not demand dosing precision. Practitioners empirically support the various pharmacokinetic and pharmacologic-based approaches described here.

New positron emission tomography tracer [11C]carvedilol reveals P‐glycoprotein modulation kinetics

Imaging of P-glycoprotein (P-gp) function in the blood-brain barrier (BBB) may support development of strategies, which will improve drug delivery to the brain. [(11)C]verapamil has been developed as a positron emission tomography (PET) tracer, to image P-gp function in vivo. Ideally, for the purpose of brain imaging, tracers should have a log P between 0.9 and 2.5. The beta-receptor antagonist carvedilol is a P-gp substrate with a log P=2.0, and can be labeled with [(11)C]. The aim of this study was to determine whether the P-gp substrate [(11)C]carvedilol can be used as a PET tracer for visualisation and quantification of the P-gp function in the BBB. Cellular [(11)C]carvedilol accumulation in GLC(4), GLC(4)/P-gp, and GLC(4)/Adr cells increased three-fold in the GLC(4)/P-gp cells after pretreatment with cyclosporin A (CsA) whereas no effect of MK571 could be determined in the GLC(4)/Adr cells. Ex vivo [(11)C]carvedilol biodistribution studies showed that [(11)C]carvedilol uptake in the brain was increased by CsA. [(11)C]carvedilol uptake in other organs was not affected by CsA. Autoradiography studies of rat brains showed that [(11)C]carvedilol was homogeneously distributed over the brain and that pretreatment with CsA increased [(11)C]carvedilol uptake. In vivo PET experiments were performed with and without P-gp modulation by CsA. P-gp mediated transport was quantified by Logan analysis of the PET data, calculating the distribution volume (DV) of [(11)C]carvedilol in the brain. Logan analysis resulted in excellent fits, revealing that [(11)C]carvedilol is not trapped in the brain. Brain DV of [(11)C]carvedilol showed a dose-dependent increase of maximal three-fold after CsA pretreatment. Above 15 mg kg(-1), no change in DV was found. Compared to [(11)C]verapamil less CsA was needed to reach maximal DV, suggesting that [(11)C]carvedilol kinetics is a more sensitive tool to in vivo measure P-gp function.

Intravenous Voriconazole Therapy in a Preterm Infant

A preterm infant younger than 3 months developed a disseminated fluconazole-resistant Candida albicans infection that was treated with liposomal amphotericin B for 52 days, followed by the combination of intravenous voriconazole and liposomal amphotericin B for an additional 19 days. The infant received concomitant phenobarbital throughout the hospital stay. The infection resolved after addition of voriconazole to the treatment regimen. Intravenous voriconazole was begun at a high dosage, 6 mg/kg every 12 hours, for anticipated developmental and drug-induced changes in volume of distribution and clearance. On day 4 of therapy, serum concentrations of voriconazole were 3.27 microg/ml immediately after infusion and 0.33 microg/ml 6 hours after infusion. These levels were significantly lower than those achieved in adult pharmacokinetic and safety studies. After the infant's dosage was increased to 6 mg/kg every 8 hours, serum concentrations were 5.33 microg/ml 30 minutes after infusion and 2.67 microg/ml 6 hours after infusion. These levels were similar to those observed in adults. Intravenous voriconazole 6 mg/kg every 8 hours was administered safely, with concomitant phenobarbital therapy, in this preterm infant with developmentally diminished renal function.

Prospective dose prediction for FXa inhibitor otamixaban (OTAM) using PK/PD simulations accounting for non-dose proportional plasma exposure

Background/Aims OTAM is a direct and selective FXa inhibitor under development for treatment of Acute Coronary Syndrome (ACS). This work describes PK/PD modeling and simulations to predict doses for dose-ranging Phase II study with target Ceoi of 75 to 600 ng/mL (MTD). Methods Plasma concentrations-time data from 3 Phase I/II studies were fitted simultaneously to a two-compartment model using WINNONLIN. The change in plasma clearance and volume of distribution with dose was accounted by introducing a linear equation for the change in volume of distribution as a function of the infusion rate. Furthermore, because a linear relationship exists between PK and PD clotting time markers (aPTT, PT, and RVVT), PK concentrations were sufficient to predict PD. Results Simulated mean concentrations were well separated for each dose. The combined 1 min/3 h infusions allowed target Ceoi to be reached immediately, with a “dip” not exceeding 20% of Ceoi. Conclusions Predictable PK/PD model allowed for optimal dose selection for the Phase II study. Figure 1. Download figure to PowerPoint (see Table) Clinical Pharmacology & Therapeutics (2005) 77, P40–P40; doi: 10.1016/j.clpt.2004.12.047 Table 1. Target Plasma Concentration ng/mL Dosage Predicted Plasma Concentration at Time Post- start of Infusion (ng/mL) Group Bolus mg/kg Infusion mg/kg/h 1 min 10 min 0.75 h 3 h 4 h 5 h 75 1 0.025 0.035 153 106 71 75 38 24 150 2 0.045 0.065 275 193 133 146 70 44 300 3 0.080 0.120 481 361 256 301 127 80 450 4 0.120 0.160 736 526 383 448 174 110 600 5 0.140 0.200 861 632 494 617 215 135

Alteration of Drug Kinetics in Rats following Exposure to Trichloroethylene

The effect of trichloroethylene (TCY) was investigated to determine whether repeated exposure alters the pharmacokinetics of some drugs. Sprague-Dawley rats were given intraperitoneal injections of TCY (5 mmol/kg) in corn oil once daily for 3 days, while the control group received only corn oil. Four hours after the last dose, theophylline, quinidine, or pentobarbital were administered. Blood samples were collected at appropriate intervals for drug analyses. There was a small decrease in plasma clearance of theophylline, with no change in volume of distribution (V_d) as compared with controls. For quinidine, the elimination half-life was unchanged, and the V_d was decreased by 40%. The clearance of pentobarbital was decreased by 40% in male rats, but not in the females. Nonetheless, the duration of the sleeping time for both sexes was remarkably prolonged as compared with the control group. There was a decrease in the cytochrome P-450 content only in male rats. In conclusion, exposure to TCY causes changes in some drug kinetics, probably resulting from differential effects on the drug-metabolizing enzymes.

Hepatic perfusion parameters in chronic liver disease: dynamic CT measurements correlated with disease severity.

The aim of our study was to determine if hepatic perfusion parameters measured with CT change in relation to disease severity in patients with chronic liver disease. Dynamic contrast-enhanced single-section CT scans of the liver were obtained in 40 individuals who included six control subjects, 16 patients with noncirrhotic chronic liver disease, and 18 patients with cirrhosis. Hepatic, aortic, and portal venous time-density curves were fitted to a dual-input one-compartment model to calculate the liver perfusion, arterial fraction, distribution volume, and mean transit time. Liver perfusion decreased in patients with cirrhosis (67 +/- 23 mL. min(-1). 100 mL(-1) versus 108 +/- 34 mL. min(-1). 100 mL(-1) in control subjects [p = 0.009] and 98 +/- 36 mL. min(-1). 100 mL(-1) in patients with noncirrhotic chronic liver disease [p = 0.003]), and the arterial fraction and the mean transit time increased (41 +/- 27% and 51 +/- 79 sec versus 17 +/- 16% and 16 +/- 5 sec in control subjects, and 19 +/- 6% and 17 +/- 8 sec in patients with noncirrhotic chronic liver disease [p < 0.05]). A significant correlation was seen between these three perfusion parameters and the severity of chronic liver disease based on clinical and biologic data (p < 0.001). No significant change in distribution volume was observed. Hepatic perfusion parameters measured with CT were significantly altered in cirrhosis and correlated with the severity of chronic liver disease.

Stereoselective pharmacokinetics of ifosfamide in male and female rats.

The stereoselective pharmacokinetics of ifosfamide (IF) were investigated in male and female Sprague-Dawley rats. Following intravenous administration of IF deuterium-labeled pseudoracemates into rats at 40 mg/kg, IF enantiomers and their metabolites, 4-hydroxyIF (HOIF), N2-dechloroethylIF (N2D), N3-dechloroethylIF (N3D), and isophosphoramide mustard (IPM) were quantitated in plasma and urine using gas chromatographic-mass spectrometry techniques with appropriately deuterium-labeled analogs as the internal standards. In addition, the intrinsic clearances of IF isomers in rat liver microsomes were estimated by the in vitro metabolism study. Following drug administration in male rats, (R)-IF exhibited a lower area under the curve value and a shorter half-life of 34.2 minutes than (S)-IF, which gave a half-life of 41.8 minutes. In female rats, the half-lives of (R)- and (S)-IF were found to be 62.1 and 75.1 minutes, respectively, significantly longer than those in male rats. No change in volume of distribution or renal clearance for IF enantiomers in all rats was observed, and the protein binding value was low, with no enantioselectivity. Both in vitro and in vivo studies showed that metabolism of (R)-IF proceeded in favor of the 4-hydroxylation pathway, whereas (S)-IF preferentially underwent N2- and N3-dechloroethylation. The observed stereoselectivity and gender difference in pharmacokinetics of IF in the rat are mainly attributed to its stereoselective metabolism.

Urine Output Predicts Serum Gentamicin Concentration in Preterm Infants 1086

There are no reliable predictors of gentamicin (G) levels in premature infants. As G is excreted by the kidneys, we hypothesized G levels can be predicted by urine output. We conducted a retrospective study of neonates(gestational age (GA)=30-36wks, n=18) who received G therapy (3 mg/kg/day). Infants with a diagnosis of acute tubular necrosis, asphyxia, hypotension or who received vasopressor support or indomethacin were excluded. We collected data on GA, body weight, urine output (UOP, cc/m2/hr), fluid intake and output(I/O), G intervals/route, body surface area, G levels and day of life G levels drawn. Data were analyzed by student's test, chi square test, correlation coefficient as appropriate. Results showed urine output ≥2 and ≤4.0 cc/k/hr predicted therapeutic G levels (peak= 5-10 mcg/mL) in premature infants (sensitivity 0.69, specificity 1 and positive predictive value 1). Urine output >4 cc/k/hr resulted in levels < 5 mcg/mL. There were significant inverse correlations between peak G levels and UOP (Fig 1) and balance of I/O (Fig 2). We conclude that urine output, 24hrs prior to G level measurement, is a non-invasive, highly predictive parameter of adequacy of dose. We also conclude that the inverse correlation of peak G levels with urine output reflects the change in volume of distribution (balance of I/O).

A New Polymethylmethacrylate Membrane for Hemodialysis

High molecular weight (MW) solutes are not removed during conventional hemodialysis (HD), and their accumulation is thought to play a role in some long-term HD complications (anemia, bone and joint pain, neuropathy, itching). The present trial was conducted to evaluate the removal capacity during in vivo HD of a new polymethylmethacrylate (PMMA) membrane (Filtryzer BK-F, 1.3 m2) compared to conventional PMMA (BK-P, 1.6 m2) and to cellulose acetate (CA, 1.3 m2). BK-F dialyzers, with a pore size of 100 A degrees and 62% porosity, are designed to remove high MW substances. Ten stable anuric RDT patients (53 +/- 13 years) were treated for one week with each membrane in a randomized sequence. Plasma concentrations of creatinine, BUN and beta 2-microglobulin (beta 2-M) were measured before (b) and after (a) HD to determine the reduction rate for these substances (%). Beta 2-M concentration after HD was corrected for changes in distribution volume. Samples of spent dialysate were collected after 3 minutes, 120 minutes and at the end of HD sessions, and appropriately treated and concentrated for HPLC analysis. The reduction rate for BUN and creatinine was similar for the 3 membranes. BK-F showed a higher beta 2-M reduction rate than BK-P (p < 0.005) or CA (p < 0.0001). HPLC analysis of dialysate showed prevalent peaks < 4 kilodaltons (kDa) throughout HD for BK-P and CA. Solutes > 10 kDa were infrequently detected. Peak profile during HD with BK-F was quite different, showing a predominant peak > 50 kDa which also included albumin. However, albumin loss significantly decreased after 120 minutes and at the end of dialysis compared with the 3-minute values, and was lower than that reported in CAPD patients. With BK-F a peak of MW > 500 kDa was also detected which previous studies indicated as a range characterized by the presence of erythropoiesis inhibitors. Use of the BK-F membrane in HD could afford satisfactory removal of high MW substances, thereby preventing or controlling some long-term HD complications such as anemia or beta 2-M amyloid formation.

Pulmonary distribution of alfentanil and sufentanil studied with system dynamics analysis.

We applied a system dynamics approach to the study of the pulmonary distribution of alfentanil and sufentanil in anesthetized pigs and patients, respectively. This method allows estimation of the mean transit time through the lungs and calculation of the volume of distribution of alfentanil in the lungs. In the first part of the study the pulmonary distribution of alfentanil was studied in six anesthetized pigs during three hemodynamic states (control, partial clamping of the inferior vena cave, and complete clamping of the right pulmonary artery). In the second part of the study the pulmonary distribution of sufentanil was studied in 10 patients, scheduled for elective CABG, during and after a constant rate infusion of 10 min. Pulmonary passage of the opioids was characterized by functions of transit times, derived from the pulmonary arterial and systemic arterial concentration curves. Pulmonary distribution volumes were calculated from the mean transit time and pulmonary blood flow. Pulmonary distribution volume of alfentanil during the control measurement was significantly higher (486 +/- 88 ml) than during either partial caval clamping (346 +/- 89 ml, p < 0.05) or right pulmonary artery clamping (336 +/- 56 ml, p < 0.05). There was no change in the extravascular volume of distribution of alfentanil with each hemodynamic state. Pulmonary volume of distribution of sufentanil in the patients was 22.6 (10.9) L. Pulmonary distribution of opioids can be studied using system dynamics analysis, both after bolus injection and during and after infusion. This method can be used for periods beyond the initial passage of the drug through the lungs.

Pharmacokinetic Origin of Carbamazepine-induced Resistance to Vecuronium Neuromuscular Blockade in Anesthetized Patients

Patients receiving chronic carbamazepine therapy have shortened recovery times from a neuromuscular block induced by vecuronium. The current study investigates the pharmacokinetic or pharmacodynamic mechanisms responsible for this observation. Pharmacokinetics and pharmacodynamics of 0.1 mg/kg intravenous bolus vecuronium in ten epileptic patients receiving chronic carbamazepine therapy were compared to that of ten control subjects. All patients were scheduled for neurosurgery while anesthetized with isoflurane and sufentanil. Arterial blood samples were collected for 6 h. Plasma vecuronium concentrations were measured by high-performance liquid chromatography coupled to electrochemical detection. The adductor pollicis force of contraction was recorded after supramaximal ulnar nerve stimulation. Plasma vecuronium concentrations were fitted to a two-compartment pharmacokinetic model, and the effect compartment equilibration rate constant was derived with a nonparametric link model. The effect compartment concentrations were fitted to a sigmoid Emax model. Results were compared using Student's t-test for independent samples. In the carbamazepine group, the mean recovery times to T(1) 25% were shorter (28.1 +/- 3.4 vs. 47.3 +/- 5.1 min in control subjects; P=0.007), and the T(1) 25% to T(1) 75% recovery index was decreased (7.6 +/- 1.2 vs. 21.9 +/- 6.8 min in control subjects; P=0.025). No changes in onset times were observed. Clearance was 9.0 +/- 1.2 ml x kg-1 x min-1 versus 3.8 +/- 0.3 in the control group (P=0.003), whereas no changes in volumes of distribution at steady-state were observed. Therefore, the mean residence time was halved (17.8 +/- 2.5 vs. 31.9 +/- 2.5 min in control subjects; P=0.001). No differences in the effect compartment equilibration rate constant, vecuronium effect compartment concentration present at a 50% block (EC50), or slope of the sigmoid between the two groups were found. The twofold increase in clearance provides evidence of a pharmacokinetic origin to the carbamazepine-vecuronium interaction; however, the possibility of a concurrent pharmacodynamic alteration cannot be assessed. Greater knowledge of protein drug binding needs to be acquired to give a meaningful interpretation to the similar EC50 values observed in the two groups.

Optimal Intravenous Dosing Strategies for Sedatives and Analgesics in the Intensive Care Unit

Achieving and maintaining adequate levels of analgesia and sedation in critically ill patients is a fundamental part of ICU care. Understanding the clinical pharmacology of commonly used sedative agents (e.g., midazolam, lorazepam, and propofol) and opioids (e.g., fentanyl and morphine) enables clinicians to best dose these drugs to the desired clinical effect while minimizing the risk of excessive sedation and cardiopulmonary depression. This has significant safety and cost implications for patient care in the ICU. Simulations of plasma concentrations of these medications when administered to ICU patients provide useful insight into the clinical pharmacology of these agents. A number of points should be made with regards to the interpretation of these predicted plasma concentrations, however. First, it is important to remember that PK parameters for most of these agents, with the exception of midazolam and propofol, were derived from bolus or short-term infusions administered to healthy patients, and that the PK parameters for lorazepam, fentanyl, and morphine when administered as long-term infusions to critically ill patients may vary dramatically from these initial estimates. Specifically, their volumes of distribution and elimination half-lives may prove to be significantly larger and longer, respectively, when administered to patients in the ICU. This pharmacokinetic variability may result in even longer emergence times than predicted herein following discontinuation of continuous infusions of these agents. Until similar studies in ICU patients are performed for lorazepam, fentanyl, and morphine, the clinical pharmacology of these agents in ICU patients remains uncertain. Additionally, midazolam and morphine both have active metabolites that can accumulate in critically ill patients receiving long-term infusions. These metabolites add significantly to the sedative effects of the primary compound. Other drugs with sedative effects given concurrently with any of these agents (i.e., psychotropic agents, epidural opioids, etc.) may also contribute to the sedative effects of these drugs. These studies do not account for the development of tolerance (which can occur with both benzodiazepines and opioids) or changing kinetic profiles within an individual patient over time (i.e., due to changes in volume of distribution, protein binding, or clearance). Finally, there is a high degree of interpatient variability among critically ill patients, and medication dosing must be tailored to individual patients' needs (i.e., one dose does not fit all patients). Given the uncertainty of resulting plasma concentrations with long-term administration of these medications, the best ways to achieve and maintain optimal levels of sedation and analgesia while minimizing the risk of oversedation and side effects are to (1) initiate sedation in an incremental fashion until the desired level of sedation is achieved, then periodically (i.e., once a day) titrate the infusion rate of sedative-hypnotics and opioids downward until the patient begins to emerge from the sedative effects of these drugs; and finally gradually increase the infusion rate until the desired level of sedation is once again achieved; and (2) consider the use of a sedation scale to standardize the level of sedation to be maintained (see Table 3). The use of such a scale enables physicians to communicate to nursing staff the specific level of sedation to be achieved and maintained in an individual patient (i.e., titrate the midazolam infusion between 0 to 5 mg/hr to maintain a sedation score of 2-3; call MD for inadequate sedation, respiratory depression, or hypotension). Achieving optimal sedation and analgesia of patients in the ICU requires not only that the choice of medication(s) be appropriate for the clinical setting but also that there are specific clinical endpoints for the agents used (i.e., light versus deep sedation, continuous versus intermittent sedation, sedation with

Population pharmacokinetics of the active metabolite of nabumetone in renal dysfunction.

We determined the pharmacokinetics of 6-methoxy-2-naphythylacetic acid (6-MNA), the active metabolite of nabumetone, in normal subjects and in subjects with impaired renal function, including subjects requiring hemodialysis. Subjects received a 1000 mg oral dose of nabumetone either as a single dose or daily for 15 days. We used a noncompartmental pharmacokinetic analysis and compared those results to a population pharmacokinetic analysis performed with nonlinear mixed-effects modeling (NONMEM). The results of the two different analyses were similar. The elimination half-life increased with decreased renal function and ranged from 22 to 44 hours. The area under the curve decreased significantly at steady state, regardless of renal function. The apparent clearance determined by NONMEM analysis increased from 0.68 L/hr after a single dose to 1.13 L/hr at steady state. The apparent volume of distribution was directly proportional to the nonalbumin protein concentration and ranged from 23 to 60 L. We conclude that the pharmacokinetics of 6-MNA in this population are complicated by possible protein binding changes. However, the increased half-life in patients with renal failure is offset by changes in the apparent volume of distribution that prevent the accumulation of 6-MNA in the serum of patients with impaired renal function. Therefore dosage adjustments may not be necessary in patients with decreased renal function.

Chronobiological Evaluation of the Active Biliary and Renal Secretion of Ampicillin

This study was carried out to determine the circadian rhythm of active renal and biliary excretion of ampicillin. Sprague-Dawley male rats, housed under a light-dark (12 h: 12 h) cycle, were used in these studies. Rats received an i.v. bolus of ampicillin (50 mg/kg) at 0800, 1200, 1600, 2000, 2400, and 0400. Plasma, bile, and urine were collected. There was a significant circadian rhythm in the renal and biliary clearances of ampicillin. Clearance was increased approximately twofold during the active cycle compared with the resting cycle. No change in volume of distribution was noted. Therefore, the mean residence time of ampicillin was significantly lower during the active cycle. Since the majority of ampicillin that is excreted into the urine and bile is actively secreted via the anion carrier-mediated pathway, the circadian rhythm of glomerular filtration cannot explain the variation observed in this study. Changes in renal/hepatic blood flow could explain, in part, the circadian rhythm observed in the...

Effect of omeprazole on diazepam disposition in the rat: in vitro and in vivo studies.

The inhibitory effects of omeprazole on diazepam metabolism in vitro and in vivo are compared in the rat. 3-hydroxylation and N-demethylation of diazepam was investigated in the presence of a range of omeprazole concentrations (2-500 microM) in hepatic microsomes and hepatocytes. Zero order infusions together with matched bolus doses of omeprazole were used to achieve a range of steady state plasma concentrations (10-50mg/L) and to study the diazepam-omeprazole interaction in vivo. The 3-hydroxlation pathway was more prone to inhibition (KIs 108 +/- 30 and 28 +/- 11 microM in microsomes and hepatocytes, respectively) than the demethylation pathway (KIs of 226 +/- 76 and 59 +/- 27 microM in microsomes and hepatocytes, respectively). In both in vitro systems, the mechanism of inhibition was competitive with Km/KI ratios larger than 1 for the 3HDZ pathway and smaller than 1 for the NDZ pathway. There was an omeprazole concentration dependent decrease in diazepam clearance in vivo which could be modelled using a simple inhibition equation with a KI of 57 microM (19.8mg/L). In contrast there was no statistically significant change in the steady state volume of distribution for diazepam in the presence of omeprazole. The in vivo KI for the omeprazole: diazepam inhibition interaction shows closer agreement with the KI values obtained in hepatocytes than with those observed in microsomes.

Effects of Blood Flow on [11C]Raclopride Binding in the Brain: Model Simulations and Kinetic Analysis of PET Data

To assess the stability of different measures of receptor occupancy from [11C]raclopride (a D2 antagonist) studies with positron emission tomography, we analyze data from five test/retest studies in normal volunteers in terms of individual model parameters from a three-compartment model, the distribution volume (DV) and the ratio of DVs from a receptor-containing region of interest to a non-receptor-containing region. Large variations were found in the individual model parameters, limiting their usefulness as an indicator of change in receptor systems. The DV ratio showed the smallest variation. Individual differences were reflected in the greater intersubject variation in DV than intrasubject variation. The potential effects of blood flow on these measurements were addressed both experimentally and by simulation studies using three models that explicitly incorporate blood flow into a compartmental model that also includes receptor-ligand binding. None of the models showed any variation in the DV with changes in blood flow as long as flow was held constant during the simulation. Experimentally, blood flow was significantly reduced by hyperventilation in a human subject. The DV was found to be reduced relative to baseline in the hyperventilation study, but the DV ratio remained unchanged. The effect of elevated and reduced flow was also tested in two baboon experiments in which PCO2 was varied. Some variability in the DV ratio was observed but was not correlated with changes in blood flow. This raises the possibility that other factors indirectly related to changes in blood flow (or PCO2) may cause changes in DV, and these effects need to be considered when evaluating experimental results.

Influence of Aging on the Pharmacokinetics and Pharmacodynamics of Doxacurium

Doxacurium (30 micrograms/kg) pharmacokinetics and pharmacodynamics were evaluated in nine elderly (age range, 70 to 83 years) and nine young (age range, 19 to 39 years) patients under nitrous oxide-isoflurane anesthesia. The force of contraction of the adductor pollicis was monitored and plasma samples were collected for an 8-hour period. In the elderly group, doxacurium elimination half-life was prolonged (119.7 versus 75.9 minutes) and plasma clearance was significantly reduced (1.75 versus 2.54 ml/min/kg) without any change in volume of distribution. Onset (12.9 versus 8.9 minutes) and recovery times (113.4 versus 48.1 minutes) were longer in the elderly group. The equilibrium rate constant to the effect compartment (kco) was decreased in the elderly (0.039 versus 0.051 min-1), whereas the effect compartment concentration at 50% block was similar in both groups (44.7 versus 54.1 ng/ml). An age-related reduction in muscle blood flow may be responsible for the decrease in kco. The pharmacokinetic changes observed in the elderly are consistent with a decreased function in the organs of elimination.

Role of Quinone Reductase in in Vivo Ethanol Metabolism and Toxicity

Quinone reductase (QR), in the presence of suitable substrate. results in the regeneration of NAD + from NADH. To test the hypothesis that QR can play a role in ethanol metabolism and toxicity, we studied the effect of a quinone as well as of induced levels of QR on ethanol administered in vivo to male rats and mice. Butylated hydroxyanisole (BHA) is known both to induce QR and to be metabolized to tert-butyl quinone (TBQ). Dietary BHA (0.75% for 10 days), followed by oral ethanol (4 g/ kg, by gavage), increased the rate of ethanol disappearance and decreased the area under the curve (AUC) for blood ethanol in both rats and mice. In addition, BHA pretreatment of rats was shown to prevent ethanol-induced 24-hr hepatic triglyceride accumulation. Also, in rats, TBQ (5 mg/kg, ip) led to decreased AUC and hepatic triglyceride accumulation, although the ethanol disappearance rate was not significantly affected. TBQ in BHA-fed rats resulted in even greater effects on the ethanol disappearance rate and AUC than TBQ or BHA treatment alone. None of these treatment regimens resulted in a significant change in volume of distribution of ethanol. Thus, these results support the hypothesis that induction of QR and/or administration of quinones leads to enhanced in vivo metabolism of ethanol and decreased hepatotoxicity.

Codeine disposition in sickle cell patients compared with healthy volunteers.

The pharmacokinetics of codeine were determined after oral administration of codeine sulfate (60 mg) with sickle cell patients (SCPs) and healthy controls (HCs). Plasma concentrations of codeine were measured by reversed-phase high-pressure liquid chromatography with fluorescence detection. Pharmacokinetic parameters were calculated using both compartmental and noncompartmental analysis. No significant differences were observed in time to reach maximum peak plasma concentration (tmax) (1.0 +/- 0.4 versus 1.4 +/- 1.0 hours), maximum peak plasma concentration (Cmax) (172 +/- 25 versus 225 +/- 97 ng/mL), area under the curve (AUC infinity) (590 +/- 96 versus 779 +/- 234 ng*h/mL), and Cl/F (104 +/- 17 versus 89 +/- 27 L/h) between SCPs and HCs. Conversely, significant differences were observed in mean residence time (MRT) (3.7 +/- 0.3 versus 4.7 +/- 0.3 hours) and half-life (t1/2) (1.7 +/- 0.2 versus 2.8 +/- 0.3 hours). In a separate study, significant differences were observed in the in vitro plasma protein binding of codeine in SCPs (66.0 +/- 8.6%) and HCs (30.5 +/- 2.7%) as well as in vivo binding (68.4 +/- 11.1% for SCPs versus 29.2 +/- 3.4% for HCs). Codeine is a relatively high-extraction drug that is primarily eliminated by metabolism in the liver. Generally, the clearance of such drugs is approximately equal to hepatic blood flow and is not affected by changes in protein binding. Therefore, the change in t1/2 observed in SCPs can be attributed to changes in volume of distribution rather than clearance.

Influence of aging on the pharmacokinetics and pharmacodynamics of doxacurium

Doxacurium (30 micrograms/kg) pharmacokinetics and pharmacodynamics were evaluated in nine elderly (age range, 70 to 83 years) and nine young (age range, 19 to 39 years) patients under nitrous oxide-isoflurane anesthesia. The force of contraction of the adductor pollicis was monitored and plasma samples were collected for an 8-hour period. In the elderly group, doxacurium elimination half-life was prolonged (119.7 versus 75.9 minutes) and plasma clearance was significantly reduced (1.75 versus 2.54 ml/min/kg) without any change in volume of distribution. Onset (12.9 versus 8.9 minutes) and recovery times (113.4 versus 48.1 minutes) were longer in the elderly group. The equilibrium rate constant to the effect compartment (kco) was decreased in the elderly (0.039 versus 0.051 min-1), whereas the effect compartment concentration at 50% block was similar in both groups (44.7 versus 54.1 ng/ml). An age-related reduction in muscle blood flow may be responsible for the decrease in kco. The pharmacokinetic changes observed in the elderly are consistent with a decreased function in the organs of elimination.