Safety,pharmacokinetic and pharmacodynamic properties of single ascending dose and continuous infusion of remimazolam besylate in healthy Chinese volunteers

The aim of the present study was to evaluate the safety, pharmacokinetic (PK) and pharmacodynamic (PD) properties of remimazolam besylate following single ascending dose (SAD) and continuous infusion in healthy Chinese volunteers. This was a randomized phase I study conducted in two parts. Part I was a double-blind, placebo- and midazolam-controlled, SAD study among healthy Chinese participants with a remimazolam dose of 0.025–0.4 mg/kg. Part II was an open-label, midazolam-controlled, continuous infusion study. Bispectral index (BIS) monitoring and Modified Observers Assessment of Alertness and Sedation (MOAA/S) score assessment were used to assess the PD properties. The half-life range of remimazolam was from 34.1 ± 8.1 to 59.8 ± 20.5 min in the SAD study. The sedation function was initially observed at the dose of 0.05 mg/kg remimazolam. Doses of ≥ 0.075 mg/kg exerted a peak sedation effect within 1–2 min after injection, resulting in a deeper and more rapid sedation. In the 2 h continuous infusion, remimazolam showed a deeper sedation and more rapid recovery than midazolam. For general anesthesia, an induction dosage of 0.2 mg/kg/min and a maintenance dosage of 1 mg/kg/h can achieve a satisfactory efficacy effect. Remimazolam was safe and well tolerated in healthy Chinese participants. Based on the phase I clinical study, we suggest that remimazolam besylate demonstrates greater sedation and quicker recovery from sedation than midazolam.     

Thrombolytic properties of a novel modified human tissue-type plasminogen activator (E6010): a bolus injection of E6010 has equivalent potency of lysing young and aged canine coronary thrombi.

The thrombolytic properties of a novel modified human tissue plasminogen activator (E6010), in which cystein 84 in the epidermal growth factor domain is replaced by serine and that has a prolonged biological half-life, were examined. The thrombolytic efficacies of E6010 and recombinant human tissue plasminogen activator (rt-PA) on the duration of coronary artery thrombus were evaluated in a canine model (123 anesthetized dogs) with copper coil-induced left anterior descending coronary artery thrombus. Thrombi established for periods of 1, 3, or 6 h, as documented by coronary arteriography, were employed. A single bolus i.v. injection of E6010 or rt-PA and an i.v. infusion of rt-PA over 60 min were compared (n = 6). Thrombolytic efficacy was evaluated by three criteria: time to reperfusion (TR), reperfusion rate at 60 min (RR), and reocclusion rate at 60 min after reperfusion (OR). With a bolus i.v. injection of E6010 at a dose of 0.2 mg/kg or an i.v. infusion of rt-PA at a dose of 0.6 mg/kg/h, these parameters were as follows: TR, 30.0 +/- 15.3 and 27.5 +/- 4.8 min; RR, 100 and 100%; OR, 17 and 33% for 1-h aged thrombi; TR, 30.0 +/- 9.5 and 35.0 +/- 8.2 min; RR, 83 and 50%; OR, 20 and 67% for 6-h aged thrombi. These data indicate that a bolus injection of E6010 is almost equally efficacious in lysing thrombi aged both 1 and 6 h. On the other hand, in the case of rt-PA, the thrombi aged 6 h were lysed significantly less than the thrombi aged 1 h. Plasma half-lives of E6010 were t1/2 alpha, 4.8 +/- 0.95 (estimated by antigen level) and 3.0 +/- 0.78 min (estimated by activity), and t1/2 beta, 51 +/- 5.4 (antigen level) and 22 +/- 7.0 min (activity). The half-lives of rt-PA were t1/2 alpha, 3.6 +/- 0.23 (antigen level) and 2.1 +/- 0.61 min (activity), and t1/2 beta, 36 +/- 2.3 (antigen level) and 7.0 +/- 3.5 min (activity). We conclude that a bolus injection of E6010 may have a more potent and longer-lasting effect than i.v.-infused rt-PA in clot lysis therapy.     

Time-Dependent Disposition of β-Naphthoflavone in the Rat

The pharmacokinetics of -naphthoflavone (BNF) have been investigated in rats following various modes of intravenous administration. From intravenous bolus studies it was established that BNF showed a high blood clearance (130 ml/min/kg) and no detectable excretion of unchanged compound in the urine. The volume of distribution for BNF was large (6 L/kg), and binding to plasma proteins extensive (96%). Intravenous infusion studies where the length of infusion was increased from 1 to 8 hr showed marked signs of time-dependent pharmacokinetics. During continuous infusions the plasma concentrations accrued for approximately 1 hr, after which plasma concentrations declined in an apparent exponential fashion to a plateau value. In the short infusion studies the postinfusion half-life (27 min) was significantly shorter than the terminal half-life after bolus administration (40 min). Time-dependent clearance of BNF resulting from enhancement/induction of P450IA enzymes is proposed as the mechanism for these unusual pharmacokinetic features. The use of antipyrine as an independent probe for P450 activity gave similar trends in antipyrine clearance for various modes of BNF administration. Computer simulations based on an autoinduction model for time-dependent clearance were consistent with the observations on BNF in the rat.     

No effect of diltiazem on the hepatic clearance of indocyanine green in the rats

In order to investigate the effect of the pretreatment with various doses of diltiazem (DTZ) on the pharmacokinetics of indocyanine green (ICG) at steady state, especially the hepatic blood clearance due to the change of hepatic blood flow, the following experiments were carried out with ICG, a hepatic function test marker, not metabolized in liver and only excreted in bile. The intravenous bolus injection (3,780 μg/kg) and the constant-rate infusion (10, 100 μg/kg/hr) or ICG into the left femoral vein were made in order to check the steady-state plasma concentration (C _ss of 10 μg/ml) of ICG at 20, 25 and 30 min. Following a 90-min washout period, the intravenous bolus injection (108, 430, 860 and 1,720 μg/kg) and the constant-rate infusion (108, 433, 866 and 1,730 μg/kg/hr) of DTZ into the right femoral vein were made and the achievement of the steady-state plasma levels (C _ss of 50, 200, 400 and 800 ng/ml) of DTZ were conformed at 60, 70 and 80 min. During the steady state of DTZ, the intravenous bolus injection (3,780 μg/kg) and the constant-rate infusion (10,200 μg/kg/hr) of ICG into the left femoral vein were made and also the steady-state plasma concentration of ICG was checked at 20, 25 and 30 min. The plasma concentrations of DTZ and ICG were determined using a high performance liquid chromatographic technique. At the steady state, the hepatic blood clearance of ICG was obtained from the plasma concentration and blood-to-plasma concentration ratio (R _b ) of ICG. The pretreatment with various doses of DTZ did not influence the plasma concentrations,R _B and plasma free fraction (f _p ) of ICG. So the hepatic blood clearance of ICG was independent of concentration of DTZ. The hepatic blood clearance of ICG could be affected by both hepatic blood flow and hepatic intrinsic clearance. But there was no change of the hepatic blood clearance of ICG between the control and the DTZ-pretreated rats in this study. So it may be suggested that DTZ does not influence hepatic blood flow.     

Pharmacokinetics in mice of the anti-retrovirus agent 9-(2-phosphonylmethoxyethyl)adenine.

The pharmacokinetics of 9-(2-phosphonylmethoxyethyl)adenine (PMEA), a potent inhibitor of retrovirus (i.e. human immunodeficiency virus) replication was determined in mice. Upon iv bolus administration of PMEA at 25, 100, or 500 mg/kg, PMEA was rapidly cleared from the plasma in a monoexponential and dose-independent manner (half-life, 7-12.5 min; distribution volume, 0.30-0.36 liter/kg; total body clearance, 1.21-2.41 liters/hr/kg). Irrespective of the initial PMEA dose, 67% of unchanged PMEA was recovered from the urine of mice within 24 hr after administration of PMEA. [3H]PMEA, administered as an iv bolus injection, mainly accumulated in the kidney, liver, and lungs. Significant amounts of monophosphorylated PMEA were detected in kidney and liver, but not other tissues, at 10, 30, and 60 min after iv administration of PMEA. Low but significant levels of PMEA were attained in the brain.     

Evaluation of the cardiovascular effects of arecoline in the anesthetized dog

Arecoline has been reported to improve memory deficits, but a relatively short half-life and adverse cardiovascular effects have limited its use. The purpose of this study was to compare the cardiovascular effects of a bolus administration with those of an infusion of arecoline in anesthetized beagle dogs. Arecoline was administered either as a 15 sec bolus (group I), as a constant infusion (group II), or as an infusion after pretreatment with 0.1 mg/kg methyl scopolamine (group III). In group I, mean arterial blood pressure (MABP) was immediately reduced (i.e., which 1 min) after each dose of arecoline, but had returned to the baseline value by 5 min after doses of 0.01 to 10 μg/kg, and by 20 min after a 30 μg/kg dose. However, blood pressure was still depressed 20 min after a 100 μg/kg dose of arecolin. Cardiac output (CO) was significantly reduced only after the 30 or 100 μg/kg doses. In group II, MABP, heart rate (HR), and CO were unchanged after a 0.3 or 1.0 μg/kg/min infusion of arecoline. An infusion of 3.0 or 10 μg/kg/min produced dose-dependent decreases in MABP (–15 and –56%, respectively) and HR (–13 and –71%, respectively). CO was unchanged at 3 μg/kg/min but was reduced by 50% at 10 μg/kg/min (P < 0.05). Plasma levels of arecoline were 46.9 ± 5.5 ng/ml after an arecoline infusion of 10 μg/kg/min. Pretreatment with methyl scopolamine significantly attenuated the cardiodepression produced by 10 μg/kg/min arecoline. Moveover, infusions of 30 and 100 μg/kg/min of arecoline produced less than 40% reductions in MABP, HR, and CO. After pretreatment with methyl scopolamine, plasma arecoline levels were 29 ± 4 and 259 ± 38.7 ng/ml with an infusion of 10 or 100 μg/kg/min, respectively. These data indicate that the continuous administration of a low dose of arecoline may minimize the undesired cardiovascular effects. Pretreatment with methyl scopolamine further attenuated the cardiovascular responses produced by arecoline, suggesting that a greater therapeutic ratio may be achieved in the presence of a peripheral muscarinic blocking agent.     

Pharmacokinetics of diminazene in sheep

The pharmacokinetic behavior of diminazene in plasma after administration of 2 mg/kg i.v. and 3.5 mg/kg i.m. was studied in four healthy Dala x Ryggja rams. Following i.v. injection, the data were satisfactorily described by a tri-exponential equation; the apparent volume of distribution at the steady-state was 0.56 +/- 0.04 L/Kg (mean +/- SD; n = 4); total body clearance averaged 1.1 +/- 0.09 ml/kg/min and elimination half-life was 9.30 +/- 1.40 hr. After intramuscular administration peak plasma levels of 6.30-7.57 micrograms/ml were reached in 20 to 45 min and the mean absorption time averaged 5.83 +/- 1.61 hr. Systemic availability relative to the intravenous dose was 95.10 +/- 23.21% and mean residence time averaged 14.16 +/- 1.55 hr. The partition of diminazene between erythrocytes and plasma averaged 0.64 +/- 0.10; plasma protein binding was high (65-85%) and concentration-dependent. Based on the experimental data obtained, an initial i.m. dose of 2.5 mg/kg followed by 2 mg/kg 24 hr later should be safe and effective in cases of babesiosis and trypanosomiasis sensitive to diminazene. A preslaughter withdrawal period of 14-26 days was estimated.     

Phase I and pharmacokinetic study of etaracizumab (Abegrin™), a humanized monoclonal antibody against α<Subscript>v</Subscript>β<Subscript>3</Subscript> integrin receptor,in patients with advanced solid tumors

Summary This study assessed the safety, immunogenicity, and pharmacokinetics of etaracizumab, a monoclonal antibody directed against the α_vβ₃ integrin, in patients with advanced malignancies. Four cohorts of four patients received escalating dose of etaracizumab as a 30-min intravenous infusion, first as a single test dose, followed-up 2–5 weeks later by weekly doses. Sixteen patients with advanced solid tumors received a total of 309 cycles of etaracizumab at doses ranging 1–6 mg/kg. The mean number of weekly infusions was 19 (ranging 5–53). Frequently reported adverse events were grades 1–2 asthenia (15 patients) and infusion reactions (9 patients). At 1 mg/kg, one patient experienced grade 3 chills with the first infusion. Other grade 3 toxicities included reversible hyponatremia, hypophosphatemia and hyponatremia in one patient each at 1, 4 and 6 mg/kg, respectively. No patient experienced treatment delay/discontinuation due to an adverse event. The half-life of etaracizumab ranged 49–180 h with a nonlinear increase in terminal half-life with increasing doses. There was no objective response but five patients experienced a stable disease of >6-month duration. Etaracizumab was well-tolerated at doses up to 6 mg/kg with no evidence of immunogenicity. The safety profile of etaracizumab warrants further exploration in ongoing phase I/II trials.     

Encapsulation of doxorubicin in liposomes containing phospatidylethanol. Part III: Effect on the toxicity and accumulation of antibiotic in myocardium

The toxicity of sterically stabilized doxorubicin-containing “solid” liposomes comprising a mixture of distearoyl analogs of phospatidylcholine and phosphatidylethanol (in a 3: 2 molar ratio) was evaluated. Upon infusion of the ordinary and liposomal doxorubicin in a total dose of 12 mg/kg, the early loss of mice with implanted ascitic Ehrlich’s carcinoma was 100 and 50%, respectively, and the average lifetime of the animals treated with liposomal doxorubicin was 1.6 times longer. In comparison to the ordinary doxorubicin, administration of the liposomal preparation resulted in a lower drop of the body weight (10%) and a smaller decrease in leukocyte number (12%). The results of fluorimetric measurements showed that the accumulation of antibiotic in the cardiac muscle 15–180 min after infusion of the liposomal doxorubicin was 30–57% lower than that upon infusion of the ordinary preparation. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 3, pp. 36–38, March, 2006.     

Toxicokinetics of soman in cerebrospinal fluid and blood of anaesthetized pigs

The toxicokinetics of the four stereoisomers of the nerve agent C(±)P(±)-soman was analysed in cerebrospinal fluid (CSF) and blood in anaesthetized, spontaneously breathing pigs during a 90-min period after injection of soman. The pigs were challenged with different intravenous (i.v.) doses of C(±)P(±)-soman corresponding to 0.75–3.0 LD₅₀ (4.5, 9.0 and 18 μg/kg in a bolus injection and 0.45 μg/kg per min as a slow infusion). Artificial ventilatory assistance was given if, after soman intoxication, the respiratory rate decreased below 19 breaths/min. Blood samples were taken from a femoral artery and CSF samples from an intrathecal catheter. The concentrations of the soman isomers were determined by gas chromatography coupled with high resolution mass spectrometry. All four isomers of soman were detected in both blood and CSF samples. The relatively non-toxic C(±)P(+) isomers disappeared from the blood stream and CSF within the first minute, whereas the levels of the highly toxic C(±)P(−) isomers could be followed for longer, depending on the dose. Concurrently with the soman analyses in blood and CSF, cholinesterase (ChE) activity and cardiopulmonary parameters were measured. C(±)P(−) isomers showed approx. 100% bioavailability in CSF when C(±)P(±)-soman was given i.v. as a bolus injection. In contrast, C(±)P(−) isomers displayed only 30% bioavailability in CSF after slow i.v. infusion of soman. The ChE activity in blood decreased below 20% of baseline in all groups of pigs irrespective of the soman dose. The effect of soman intoxication on the respiratory rate, however, seems to be dose-dependent and the reason for ventilatory failure and death. Artificial ventilation resulted in survival of the pigs for the time-period studied. Received: 3 March 1998 / Accepted: 5 May 1998     

Effects of hydroxyethylstarch (Hespan), a plasma expander, on the functional activity of the reticuloendothelial system. Comparison with human serum albumin and pyran copolymer

The purpose of the present investigation was to determine if RES activity was altered after the infusion (bolus i.v. injection over approximately 3-5 min) of hydroxyethylstarch (HES). RES function was determined by vascular clearance of 51Chromium-labeled sheep erythrocytes and the subsequent uptake into the liver, spleen, lungs, and thymus at 1 hr, 3 hr, 6 hr, 1 day, 3 days, and 7 days post infusion. Infusion with the low doses of HES (20 and 40 ml/kg) produced changes in vascular clearance which were comparable to physiological saline. Infusion with 80 ml/kg HES produced a biphasic response with a modest suppression of vascular clearance (i.e., 151% increase in half life) and hepatic phagocytosis (50%) during the first 6 hours after injection, followed by recovery at 24 hours and a stimulation in hepatic uptake (42%) after 3 days. These effects by HES were compared to those produced by infusion with 80 ml/kg HSA, a comparable colloid and with 80 ml/kg pyran copolymer, a positive control.     

Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate in rabbits after intravenous administration

The pharmacokinetics of methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX), a major metabolite, were investigated in rabbits after intravenous bolus injection and infusion using a specific HPLC assay. The arterial sampling (from the carotid artery) was used in all the studies since peculiar and significant arterial-venous differences in the plasma concentration of MTX and 7-OH-MTX were found following bolus administration of the drug. The disposition kinetics of MTX appeared polyexponential with a small terminal phase having a half-life of 10.2–27.5 hr. Extensive formation of 7-OH-MTX occurred at the two dose levels (15 and 50 mg/kg). Nonlinear disposition of MTX was reflected in several aspects of data analysis. A disproportionate increase in the AUC with dose was observed. An increase in dose not only reduced the mean total body clearance (7.49 vs. 4.26 ml/min/kg) and renal clearance (4.89 vs. 2.76 ml/min/kg), but also prolonged the mean residence time (26.2 vs. 43.3 min). The steady-state volume of distribution (V_ss) of MTX was estimated to range from 0.16 to 0.25 L/kg. More than 90% of the dose was excreted as MTX and 7-OH-MTX within 8 hr after dosing. Renal clearances decreased with the increasing plasma levels, suggesting active tubular secretion as one of the excretion mechanisms. A similar pattern for renal clearance of 7-OH-MTX was obtained. Infusion studies of 7-OH-MTX revealed that this metabolite had a longer residence time and a larger V_ss as compared with MTX, which were in accordance with its physicochemical properties. Essentially complete doses of 7-OH-MTX could be recovered in the rabbit urine.     

Plasma kinetics of DDAVP in man

After a bolus injection, DDAVP was infused in normal volunteers over a period of 3 1/2 hours. Blood was sampled during and after the infusion and was analyzed for DDAVP using a specific RIA. The total clearance for DDAVP was 2.6 ml/min./kg b.wt., and half-life in plasma 55 min.     

Effect of intravenous dopamine infusion on plasma concentrations of dopamine and dopamine sulfate in men, during and up to 18 h after infusion

Objective: We investigated whether sulfoconjugation contributes to the inactivation of intravenously infused dopamine (DA) in low concentrations with a predominant action on the kidney. Methods: Plasma DA and dopamine sulfate (DA-S) concentrations were determined during 4 h of intravenous infusion of DA (2 μg/kg/min) and up to 18 h after cessation of infusion. Twenty-seven healthy young subjects participated in the placebo controlled, randomised and double-blind study. Results: Intravenously administered DA was sulfoconjugated rapidly and to a great extent. After starting the infusion, DA levels rose within minutes and reached a steady state after 30–60 min. The steady-state levels averaged 151.3 ± 8.2 nmol/l. DA-S levels also increased markedly with infusion from 16.7 ± 9.9 nmol/l at the start of infusion up to 261.2 ± 24.2 nmol/l at 30 min after cessation of infusion. Plasma DA concentrations after cessation of the infusion decreased rapidly with an initial half-life of elimination of 4.8 min. Concentrations of plasma DA-S declined with a half-life of 4.5 h. Persistent elevations of free and conjugated DA compared with pre-treatment levels were observed even 18 h after cessation. Heart rate and blood pressure remained unchanged both during DA and saline infusion. Conclusion: Findings indicate that the sulfoconjugation pathway contributes markedly to the inactivation of intravenously infused DA and seems not to be saturable by DA infusion in low doses. Received: 8 March 1999 / Accepted in revised form: 21 September 1999     

The effect of eltanolone on pulmonary vascular resistance in landrace swine.

This paper reports on the haemodynamic effects of eltanolone observed in Landrace swine during the investigation of the drug with respect to safety in malignant hyperthermia-susceptible individuals. Pigs were sedated with intramuscular ketamine, followed by induction of anaesthesia employing thiopentone administered via an ear-vein. After intubation, anaesthesia was maintained using nitrous oxide in oxygen. A total of eight pigs were then further anaesthetised on two separate occasions using one of two dose schedules. A bolus of 1.5 mg kg(-1) of eltanolone was administered, followed by a continuous infusion at either 2 or 10 mg kg(-1) h(-1). There were no significant changes in heart rate, mean arterial pressure, cardiac output or systemic vascular resistance following eltanolone. In all cases eltanolone induced marked rises in pulmonary artery pressure and pulmonary vascular resistance (P<0.01) at all measuring points and in right ventricular stroke work at 6-10 min after drug exposure. We conclude that the selective influence of eltanolone on the pulmonary vasculature is probably species-specific, but may have clinical significance in patients with pulmonary hypertension.     

The Acute Toxicity of BIOLF-143 in the Rat

The Acute Toxicity of BIOLF-143 in the Rat. ECOBICHON, D. J.,MEKHAEL, K. M., MAJOR, P., AND OGILVIE, K. K. (1988). Fundam.Appl. Toxicol. 10, 313-320. BIOLF-143, an experimental, purine-basedacyclic nucleoside, was administered by iv or ip injection toyoung, adult, male and female Sprague-Dawley rats in order todetermine the (1) pharmacokinetic disposition, (2) route andrate of excretion, and (3) acute toxicity. HPLC analysis ofplasma, hepatic, and renal tissue levels was conducted followingiv injections of 50 and 100 mg/kg and ip injections of 500 mg/kg.Metabolism/excretion studies were conducted following ip injectionsof BIOLF-143 (100 mg/kg). The assessment of acute toxicity wasdone following the ip injection of agent (250 mg/kg/hr for 8consecutive hr). BIOLF-143 was rapidly distributed in the body,the estimated half-life in blood plasma being 18–23 min.The molecule was essentially unbound to plasma proteins (99%free) and was excreted unchanged in the urine. The recoveryof the parent compound was 74.3 ± 5.9/ and 88.5 ±15.9% for male and female rats, respectively, with no metabolitesor unidentifiable peaks being detected in HPLC chromatograms.No overt toxicity or untoward signs of latent toxicity wereobserved in the animals receiving doses up to 2000 mg/kg ip.No residues were detected in tissues at 24 hr post-treatment.A potential target organ in subchronic studies might be thekidney. High residue levels of BIOLF-143 were detected 1.0 hrpost-treatment; however, the organ had cleared all residuesby 24 hr after administration.     

Effect of Uridine Diphosphoglucose on Levels of 5-Phosphoribosyl Pyrophosphate and Uridine Triphosphate in Murine Tissues

The purpose of the present investigation was to determine whether a single bolus intravenous injection (2000 mg/kg) of uridine diphosphoglucose (UDPG) could affect levels of PRPP in a transplanted mammary adenocarcinoma and in liver of CD8FI mice. Six hours following a single intravenous injection of UDPG, 2000 mg/kg, tumor PRPP was lowered to 80 pmol/mg protein, a 53% decrease compared to saline control tumors. Liver was more sensitive than tumor to the 5-phosphoribosyl pyrophosphate (PRPP)-depleting effects of a single bolus intravenous injection of UDPG, since significantly lower levels of PRPP were found in liver, but not in tumor, at doses of 500–1000 mg/kg of UDPG. Maximal depression (30% of saline control) or PRPP occurred in liver 6 hr after intravenous UDPG at 1000–2000 mg/kg. Enhanced levels of UDPG in plasma (half-life less than 10 min) and tumor was detected at 30 min after intravenous UDPG at 2000 mg/kg. There was no detectable increase in endogenous levels of UDPG in liver at this time, probably as a result of rapid metabolism of UDPG by liver. At this same time, a twofold increase in uridine triphosphate (UTP) was measured in liver after intravenously administered UDPG. In contrast, the level of UTP was not increased significantly above control values in tumor. These data suggest the potential use of UDPG to elevate UTP pools in normal tissues in the delayed rescue of cancer chemotherapeutic drugs such as 5-fluorouracil which function as a uridine analogue in these tissues.     

A pharmacokinetic-pharmacodynamic model of tolerance to morphine analgesia during infusion in rats

A pharmacokinetic-pharmacodynamic (PK-PD) model was constructed to describe the kinetics of tolerance development to morphine-induced antinociception. Tail-flick latencies in response to hot water (50°C) were assessed in male Sprague-Dawley rats exposed to a 12-hr iv infusion of either morphine (1.4 to 3.0 mg/kg per hr) or saline. Morphine-induced antinociception, expressed as the percentage of maximum possible response (%MPR), peaked after 120 min of infusion and decreased thereafter despite sustained systemic morphine concentrations. Both the rate and extent of tolerance development increased with increasing concentrations; an overall residual effect of approximately 24% MPR was observed at the end of the infusion regardless of the steady-state morphine concentration. The kinetics of tolerance offset were examined in a separate experiment by assessing tail-flick latency 15 min after morphine iv bolus (2 mg/kg) in tolerant and control rats. Recovery of response neared completion 18.5 days after a 12-hr exposure to morphine (2.0 mg/kg per hr). A PK-PD model was constructed to account for the delay in onset of antinociceptive effect and tolerance development relative to the blood concentration-time profile. According to this model, both the extent and the rate of tolerance development were modulated by the kinetics of the drug in the central compartment. Accumulation of a hypothetical “inhibitor” acting either as a reverse agonist, a competitive or noncompetitive antagonist, or a partial agonist could potentially account for the loss of pharmacologic effect in the presence of an agonist. The rate of tolerance development predicted from the PK-PD model varied widely (28-fold) depending on the type of pharmacologic interaction selected to account for the loss of effect. Using the rate of tolerance offset to discriminate between the different models (t_1/2 offset 5.4 days), onset and offset of tolerance was described accurately by postulating that the inhibitor behaves as a partial agonist with low intrinsic activity (5.5% MPR) and high binding affinity for the receptor (IC₅₀ 15.0 ng/ml). Presented in part at the Seventh Annual Meeting of the American Association of Pharmaceutical Scientists, San Antonio, Texas, November 15–19, 1992.     

Absorption of 5′-Deoxy-5-fluorouridine from Colon

Rectally administered 5-deoxy-5-fluorouridine (dFUR) is active against transplanted dimethylhydrazine-induced colon tumor in rats. This study investigated the disposition of dFUR in normal non-tumor-bearing rats after rectal administration (350 or 700 mg/kg). An intravenous (iv) bolus injection of [5-³H]dFUR (28.2 µCi, 0.43 µg) was given 5 min after the rectal dose (700 mg/kg) to determine the dFUR clearance (CL). Blood and fecal samples were analyzed by high-pressure liquid chromatography and liquid scintillation. After the iv tracer dose, the CL was 19 ml/min/kg and the terminal half-life was 50 min. After a 700-mg/kg rectal dose, the terminal half-life was 430 min, the bioavailability was 30%, and the fraction of the dose recovered in 24-hr feces was 34%. After a 350-mg/kg dose, absorption was apparently not completed at 12 hr, as indicated by a lack of decline in blood concentration. The bioavailability of the 350-mg/kg dose exceeded 16%. The absorption of dFUR (700 mg/kg) from the colon was analyzed by the Loo–Riegelman method; the absorption half-life was 550 min. The terminal half-life after the rectal dose was much slower than that after the iv tracer dose but similar to the absorption half-life. These data indicate that dFUR was absorbed from the colon, that the absorption process was the rate-limiting step of its disposition after rectal administration, and that the slow absorption gave a sustained drug concentration in blood.     

Pharmacokinetics of recombinant human superoxide dismutase.

Superoxide dismutase (SOD) disposition was studied in order to design a rational approach for drug administration in the setting of acute myocardial infarction. Four chronically instrumented conscious dogs received the following dosage regimens of recombinant human SOD (rhSOD) on successive days: (a) 5 mg/kg left atrial (LA) bolus, (b) 5 mg/kg central vein (CV) bolus, (c) 15 mg/kg CV bolus, and (d) 5 mg/kg CV infusion over 60 min; additionally, all dogs received (e) a 5 mg/kg CV bolus under pentobarbital anesthesia. Serial serum samples were obtained after each dose and serial myocardial samples were obtained after dose (e). The serum rhSOD concentration was measured by radioimmunoassay and the data were fit to a two-compartment model. The distribution half-life was 7.8 +/- 1.7 min (mean +/- SEM), and the elimination half-life was 51.1 +/- 5.9 min; the central compartment volume of distribution (Vc) was 81 +/- 26 ml/kg and the steady-state volume of distribution was 156 +/- 20 ml/kg. The dosage regimen had no influence on clearance rates. Peak plasma concentrations (micrograms/ml) for the dosage regimens were (a) 65 +/- 28, (b) 89 +/- 19, (c) 214 +/- 61, (d) 20 +/- 5, and (e) 86 +/- 9. The peak level following continuous infusion did not occur until 50 min of infusion and was only one-fourth of the level achieved with a bolus of the same dose. Myocardial levels were less than 1% of serum levels, suggesting negligible rhSOD penetration into the myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)