RENAL,BILIARY AND INTESTINAL CLEARANCE OF SOTALOL ENANTIOMERS IN RAT MODEL: EVIDENCE OF INTESTINAL EXSORPTION

Biliary clearance (Cl_b ) of sotalol (STL) enantiomers was assessed in anaesthetized Sprague–Dawley rats (419±9 g, mean±SEM, n=4) following administration of a 10 mg kg⁻¹ IV dose of the racemate. Cl_b for S- and R-STL (0·0675±0·0090 and 0·0662±0·0089 mL min⁻¹ kg⁻¹, respectively) represented approximately 0·3% of systemic clearance (Cl_s ) values for S- and R-STL (20·4±2·2 and 20·7±2·0 mL min⁻¹ kg⁻¹, respectively). Bile:plasma concentration ratios at 1, 2, and 3 h post-dose were approximately 1·4, 1·3, and 1·2 for both STL enantiomers. Renal clearance (Cl_r ) and intestinal clearance (Cl_i ) of STL enantiomers were assessed in conscious Sprague–Dawley rats (325 g, n=4) following administration of a 10 mg kg⁻¹ IV dose of the racemate. STL enantiomers were predominantly eliminated intact in the urine: Cl_r for S- and R-STL (26·3±3·2 and 28·7±4·2 mL min⁻¹ kg⁻¹, respectively) accounted for approximately 96% of Cl_s for S- and R-STL (27·5±3·3 and 29·9±4·2 mL min⁻¹ kg⁻¹, respectively). Approximately 4% of the dose was recovered in the faeces, corresponding to Cl_i values of 1·16±0·17 and 1·26±0·19 mL min⁻¹ kg⁻¹ for S- and R-STL, respectively. Total recovery of the administered dose in urine and faeces was 99·7±0·2 and 99·8±0·5% for S- and R-STL, respectively. It is concluded from these results in the rat model that (i) STL enantiomers are predominantly eliminated intact in urine; (ii) STL enantiomers are excreted intact in bile, and to a much larger extent in the faeces, thus suggesting the presence of intestinal exsorption of STL; (iii) STL does not appear to be metabolized; and (iv) Cl_s , Cl_r , Cl_b , and Cl_i are negligibly stereoselective.     

p -HYDROXYMETHAMPHETAMINE ENANTIOMER PHARMACOKINETICS AND METABOLISM IN RATS: ABSENCE OF N-DEMETHYLATION

p -hydroxymethamphetamine (OHMAP) is one of the major metabolites of the widely abused drug methamphetamine (MAP). The demethylation of OHMAP to p -hydroxyamphetamine (OHAP) has been shown in vitro but has never been reported in vivo. The disposition kinetics as well as the metabolism of OHMAP was investigated employing a sensitive HPLC method which can separate the enantiomers of OHMAP and OHAP. Both conjugated and unconjugated forms of these compounds can be quantitated. Male Sprague–Dawley rats were given an iv bolus of racemic OHMAP (20 mg kg⁻¹) and serum and urine samples were collected at selected times. The serum concentration–time data for OHMAP enantiomers could be described by a biexponential equation. The clearance of D-OHMAP (93.5 mL min⁻¹ kg⁻¹) was slightly, but statistically significantly, greater than that of the L-enantiomer (83·9 mL min⁻¹ kg⁻¹). The steady-state volumes of distribution of L- and D-OHMAP were (mean ± SD) 3·15 ± 0·84 and 4·23 ± 1·76 L kg⁻¹, respectively. No significant concentrations or amounts of OHAP enantiomers could be detected in any serum or urine sample. Rats excreted more unchanged L-OHMAP (34%) than D-OHMAP (29%). In contrast, more conjugated D-OHMAP (57%) was recovered compared to the conjugated L-OHMAP (52%). The results suggest that there is slight stereoselectivity in the disposition of OHMAP enantiomers. The N-demethylation product (OHAP) was not produced in vivo. © 1997 John Wiley & Sons, Ltd.     

EXTRAHEPATIC FIRST-PASS METABOLISM OF NIFEDIPINE IN THE RAT

The peroral (po) bioavailability of nifedipine is reported to range from about 45 to 58% in the rat; this compares favourably to human beings. The metabolism of nifedipine is similar in rats and humans (oxidation of the dihydropyridine ring), with the liver believed to be solely responsible for the systemic clearance of the drug and the observed first-pass effect after po dosing. The purpose of this study was to determine whether intestinal metabolism also contributes to the first-pass elimination of nifedipine in the rat. The systemic availabilities of nifedipine doses given by po, intracolonic (ic), and intraperitoneal (ip) routes of administration were compared to that for an intravenous (iv) dose (in each case a dose of 6 mg kg⁻¹ was given) using adult male Sprague–Dawley rats (249–311 g, n =6 or 7/group). The geometric mean of systemic nifedipine plasma clearance after iv dosing was 10·3 mL min⁻¹ kg⁻¹. The nifedipine blood-to-plasma ratio was found to be about 0·59. Therefore, the systemic blood clearance of nifedipine was about 17·5 mL min⁻¹ kg⁻¹; which, compared to the hepatic blood flow of rats (55 to 80 mL min⁻¹ kg⁻¹) showed that nifedipine is poorly extracted by the liver (0·22≤E_H≤0·32). The mean absolute bioavailabilities of the po, ip, and ic doses were 61, 90, and 100%, respectively. Assuming complete absorption of the extravascular nifedipine doses these results indicate that, in addition to hepatic extraction, substantial first-pass elimination of nifedipine occurs within the wall of the small intestine but not the colon of the rat. © 1997 John Wiley & Sons, Ltd.     

Interaction between mivacurium and pancuronium: impact of the order of administration

Introduction Potentiation of mivacurium by low-dose pancuronium is mostly due to an inhibition of plasma butyryl cholinesterase (BchE) resulting in a decreased rate of hydrolysis of mivacurium. Nevertheless, an interaction at the receptor site could not be ruled out. By changing the order of the muscle relaxant injections, we may lessen the pharmacokinetic interaction and assess the impact at the acetylcholine receptor level.Methods Twenty patients scheduled for general anesthesia with propofol and fentanyl, and isoflurane were randomized into two groups receiving, mivacurium 100 g kg^–1 followed by pancuronium 15 g kg^–1 (group 1) or pancuronium 15 g kg^–1 followed by mivacurium 100 g kg^–1 (group 2). BchE before and after injection of each relaxant was measured. Neuromuscular block was assessed with a force transducer at the adductor pollicis measuring the elicited twitch to ulnar nerve stimulation.Results The neuromuscular block was greater when pancuronium was administered before mivacurium (100% versus 96±3%; P<0.05). Times to recovery of the elicited twitch response to 25% and 75% of control value were increased by 100% (P<0.05). After pancuronium, decreases in BchE of 11% and 14% in groups 1 and 2 were observed, respectivelyConclusion Interaction between mivacurium and low dose pancuronium is significant only when mivacurium is injected after pancuronium.     

PHARMACOKINETICS AND FOOD INTERACTION OF MK-462 IN HEALTHY MALES

A study was conducted to assess the safety, tolerability, and pharmacokinetics of single intravenous (IV) doses of 5–90 μg kg⁻¹of MK-462, and the effect of food on the pharmacokinetics of MK-462 administered orally to healthy males. Results of this study indicate that IV doses of MK-462 from 5 to 90 μg kg⁻¹ are well tolerated. The disposition kinetics of MK-462 were linear for IV doses up to and including 60 μg kg⁻¹. The values of the plasma clearance (CL), steady-state volume of distribution (V_ss), plasma terminal half-life (t_½), and mean residence time in the body (MRT) of MK-462 averaged 1376 mL min⁻¹, 140 L, 1·8 h, and 1·7 h, respectively, and remained essentially constant over the dosage range of 10–60 μg kg⁻¹ of IV MK-462. However, as the dose increased from 60 to 90 μg kg⁻¹, the mean value of the apparent CL decreased from 1376 to 807 mL min⁻¹. Thus, elimination of MK-462 was dose dependent in this dosage range. Based on the disposition decomposition analysis (DDA), it was shown that the V_ss value of MK-462 remained essentially constant over the dosage range of 10–90 μg kg⁻¹ of IV MK-462. The following values of two dose-independent parameters were also calculated by using DDA: distribution clearance (CL_d=2028 mL min⁻¹, and mean transit time in the peripheral tissues (MTT_T )=0·74 h. The mean values of AUC, C_max, t_max, and apparent t_½ of MK-462 in 12 subjects each receiving a 40 mg tablet of MK-462 without breakfast were 330 ng·h mL⁻¹, 77 ng mL⁻¹, 1·6 h, and 1·8 h, respectively. Although administration of a standard breakfast prior to dosing increased the AUC value (by ≈20%) of MK-462 and delayed its absorption, there were no significant effects of the meal on the values of C_max and apparent t_½ of MK-462.     

THE EFFECT OF EXPERIMENTAL RENAL FAILURE ON TOLFENAMIC ACID DISPOSITION IN THE DOG

The pharmacokinetic disposition of tolfenamic acid, an NSAID, after a single administration of tolfenamic acid (4 mg kg⁻¹) by the intravenous (IV) route was compared in eight dogs before and after a surgically induced renal failure. Renal impairment was confirmed by a significant increase ( p <0·001) of water intake, urine volume, and urea and creatinine plasma concentration. PAH and inulin clearances decreased after surgery from 15·2±4·2 to 9·5±0·8 mL kg⁻¹ min⁻¹ ( p <0·05) and from 4·37±1·15 to 2·43±0·88 mL kg⁻¹ min⁻¹ ( p =0·067), respectively. After surgery, clearance of TA was significantly ( p <0·001) increased, from 2·22±1·68 to 3·59±1·81 mL kg⁻¹ min⁻¹. There was no modification of the steady-state volume of distribution ( p >0·05) and the mean residence time was significantly decreased from 606±199 to 373±302 min ( p <0·05). No variation of binding to plasma proteins (<99%) was observed. These results suggest that renal insufficiency could increase hepatic metabolism and/or alter the enterohepatic cycle of TA. © 1997 by John Wiley & Sons, Ltd.     

Pharmacokinetics and pharmacodynamics of CI-992 following intravenous and oral administration to cynomolgus monkeys

The purpose of this study was to characterize CI-992 pharmacokinetics and pharmacokinetics/pharmacodynamics (PK/PD) in sodium deplete monkeys. Panels of monkeys were administered CI-992 as a 1 h intravenous infusions (0.1 and 1 mg kg⁻¹) or as single oral doses (0, 10, 50, and 100 mg kg⁻¹). Mean arterial blood pressure (MABP) was monitored and serial blood samples were collected up to 24 h postdose. Plasma CI-992 concentrations were quantitated by radioimmunoassay. Pharmacokinetic parameters were calculated by noncompartmental methods. PK/PD relationships were assessed by standard methods. Oral bioavailability of CI-992 in the monkeys was <2%; steady-state volume of distribution was 0.67 L kg⁻¹; clearance was 10.4 mL min⁻¹ kg⁻¹. Following oral administration, t_max generally occurred 6–9 h postadministration; plasma CI-992 concentrations increased with increasing dose between 10 and 50 mg kg⁻¹, but did not change appreciably from 50 to 100 mg kg⁻¹. After intravenous administration, change in MABP was correlated with plasma CI-992 concentration through an effect compartment model in which the maximum achievable effect was a 22 mm Hg decrease in MABP; the steady-state concentration which produced half the maximum effect was 11 ng mL⁻¹. Following the 10 mg kg⁻¹ oral dose the maximum decrease in MABP was 19.1 mm Hg; higher doses did not produce greater maximum response but increased the duration of action. In contrast to observations following intravenous administration, a trend for decreasing MABP with increasing plasma CI-992 was not apparent following oral CI-992 administration. © 1998 John Wiley & Sons, Ltd.     

Pharmacokinetic and pharmacodynamic changes of azosemide after intravenous and oral administration of azosemide to uranyl nitrate-induced acute renal failure rats

The pharmacokinetic and pharmacodynamic differences of azosemide were investigated after intravenous (IV) and oral administration of azosemide, 10 mg kg⁻¹, to the control and uranyl nitrate-induced acute renal failure (U-ARF) rats. After IV administration, the plasma concentrations of azosemide were significantly higher in the U-ARF rats and this resulted in a significant increase in AUC (2520 versus 3680 μg min mL⁻¹) and significant decrease in Cl (3.96 versus 2.72 mL min⁻¹ kg⁻¹) of azosemide. The significant decrease in Cl in the U-ARF rats was due to the significant decrease in Cl_r of azosemide (1.55 versus 0.00913 mL min⁻¹ kg⁻¹) due to the decrease in kidney function in the U-ARF rats. After IV administration, the urine output (38.5 versus 8.45 mL 100 g⁻¹ body weight) and urinary excretion of sodium (4.60 versus 0.420 mmol 100 g⁻¹ body weight) decreased significantly in the U-ARF rats. After oral administration, the AUC_{0–8 h} of azosemide decreased significantly (215 versus 135 μg min mL⁻¹) in the U-ARF rats possibly due to the decreased GI absorption of azosemide. After oral administration, the 24-h urine output decreased considerably (16.1 versus 11.2 mL 100 g⁻¹ body weight, p <0.098) and the 24-h urinary excretion of sodium (1.74 versus 0.777 mmol 100 g⁻¹ body weight) decreased significantly in the U-ARF rats. The IV and oral doses of azosemide needed to be modified in the acute renal failure patients if the present rat data could be extrapolated to humans. © 1998 John Wiley & Sons, Ltd.     

PHARMACOKINETICS AND TOXICOKINETICS OF AN ORALLY ACTIVE TRIPEPTIDE,IRI-695, IN ANIMALS

Pharmacokinetics and toxicokinetics of IRI-695, a tripeptide, were investigated in the rat, rabbit, dog, and monkey. Tissue distribution and excretion of [¹⁴C]IRI-695 were determined in the rat. Following a single intravenous (IV) injection, the elimination half-life (t_1/2) of IRI-695 in the rabbit, dog, and monkey was similar (about 65 min) and approximately four times that in the rat (15 min). This difference in t_1/2 can be attributed to about four times higher clearance of the drug in rats (11·2 mL min⁻¹ kg ⁻¹). The volume of distribution (V_ss) in these four species, 132–234 mL kg⁻¹, suggested negligible preferential distribution of IRI-695 to body tissue. After a 5 mg kg⁻¹ oral dose, the absolute bioavailability of IRI-695 was 2·0% in rats and 3·1% in dogs. However, systemic drug exposure in the dog was about five to 10 times that in the rat, which is related to the slower clearance of the peptide in the dog. Toxicokinetic studies in the rat and dog indicated linear kinetics and systemic exposure of IRI-695 up to 300 mg kg⁻¹ d⁻¹ oral doses throughout the 28 d toxicity study. Accumulation of the drug after the repeated oral dosing was negligible. After a single 0·10 mg kg⁻¹ ]¹⁴C[IRI-695 IV injection in rats, almost all of the radioactivity administered was excreted in urine within 24 h postdose.     

TISSUE-SELECTIVE UPTAKE OF PRAVASTATIN IN RATS: CONTRIBUTION OF A SPECIFIC CARRIER-MEDIATED UPTAKE SYSTEM

Previously we demonstrated that a hydrophilic HMG-CoA reductase inhibitor, pravastatin, was actively taken up by the liver via the ‘multispecific anion transporter’ using isolated rat hepatocytes (M. Yamazaki, H. Suzuki, M. Hanano, T. Tokui, T. Komai, and Y. Sugiyama, Am. J. Physiol., 264 , G36–G44 (1993)). Such a carrier-mediated uptake of pravastatin may contribute to the liver selective inhibition of the cholesterol synthesis in vivo. To examine the early-phase tissue distribution of this drug, we carried out a pharmacokinetic and tissue distribution analysis of pravastatin in rats. After i.v. bolus administration of [^;14C]pravastatin, the time profiles of [¹⁴C]-radioactivity in plasma and several tissues were determined to calculate the tissue uptake clearance (CL_uptake). Among the tissues examined, liver accounted for the major uptake (CL_{uptake, liver}=22·8 mL min⁻¹ kg⁻¹), followed by kidney (CL_{uptake, kidney} (GFR corrected)=2·36 mL min⁻¹ kg⁻¹). Other tissues showed no significant uptake (less than 0·2 mL min⁻¹ kg⁻¹). After portal vein administration, the distribution to the liver became much larger than that to the kidney due to the extensive first-pass removal by the liver. The first-pass hepatic uptake ratio was estimated as 0·66. Administering a range of doses (0·4–400 μmol kg⁻¹) intravenously, an increase in early-phase half-life and a decrease in CL_{uptake, liver} were observed simultaneously at doses over 40 μmol kg⁻¹. In addition, CL_{uptake, kidney} decreased at doses over 4 μmol kg⁻¹. The effect of DBSP or PAH co-infusion (i.e. typical substrates for the transport system for organic anions in liver and kidney, respectively) on the initial uptake of pravastatin was also examined. DBSP clearly inhibited both the hepatic and renal uptake; however, PAH did not reduce the hepatic uptake of pravastatin although it inhibited the renal uptake. The transport systems in liver and kidney are thus considered different, based on the different saturability and inhibitory effect of organic anions.     

Pharmacokinetics and tissue distribution of a new carbapenem,DA-1131, after intravenous administration to mice,rats, rabbits and dogs

The pharmacokinetic parameters including tissue distribution and/or biliary excretion of DA-1131, a new carbapenem, were evaluated after intravenous (iv) administration to mice, rats, rabbits, and dogs. After iv administration to mice (20, 50, 100, and 200 mg kg⁻¹), rats (50, 100, 200, and 500 mg kg⁻¹), rabbits (20, 50, 100, and 200 mg kg⁻¹), and dogs (10, 20, 50, 100, and 200 mg kg⁻¹), the pharmacokinetic parameters of DA-1131 seemed to be independent of DA-1131 doses studied in all four animal species. However, the renal clearance and percentage of iv dose of DA-1131 excreted in 24 h urine as unchanged drug decreased significantly in rabbits (from 200 mg kg⁻¹) and dogs (from 100 mg kg⁻¹) due to reduced kidney function induced by DA-1131. The creatinine clearance decreased significantly in rabbits at 200 mg kg⁻¹ compared with that in the control rabbits (0.466 versus 4.31 mL min⁻¹ kg⁻¹). Renal active secretion of DA-1131 was observed in rabbits and was less considerable in rats, but renal active reabsorption of DA-1131 was observed in dogs. Although DA-1131 was widely distributed in all tissues studied in mice (20–200 mg kg⁻¹), rats (200 mg kg⁻¹), rabbits (50 mg kg⁻¹), and dogs (50 mg kg⁻¹), affinity of DA-1131 for tissues was low: the tissue-to-plasma concentration ratios were greater than unity only in the kidney and/or liver. The low affinity of DA-1131 for tissues was also supported by relatively low values of the apparent volume of distribution at steady state in rats (147–187 mL kg⁻¹), rabbits (91.7–148 mL kg⁻¹), and dogs (243–298 mL kg⁻¹). The contribution of biliary excretion of unchanged DA-1131 to nonrenal clearance of DA-1131 seemed to be minor in rats (200 mg kg⁻¹) and dogs (50 mg kg⁻¹); the percentages of iv dose excreted in 8 h bile as unchanged DA-1131 were 1.76 and 2.71% after iv administration of the drug to rats and dogs, respectively. © 1998 John Wiley & Sons, Ltd.     

Sodium bicarbonate reverts electrophysiologic cardiotoxicity of ropivacaine faster than lipid emulsions in a porcine model

Ropivacaine has been described as a safer local anaesthetic (LA); however, serious cardiotoxic accidents have been reported. Intravenous-lipid-emulsion (ILE) therapy during LA intoxication seems to act as an antidote. Sodium bicarbonate is the standard treatment for sodium channel blocker drug toxicity. We compared both antidotes on the reversion of electrophysiologic toxicity induced by ropivacaine. Ropivacaine 5 mg kg⁻¹ was administered in 24 pigs, and 3 min later, the animals received ILE: 1.5 ml kg⁻¹ + 0.25 ml kg⁻¹ min⁻¹ (ILE group); sodium bicarbonate: 2 mEq kg⁻¹ + 1 mEq kg⁻¹ h⁻¹ (NaHCO₃ group); saline solution (CTL group). Electrophysiological parameters were evaluated for 30 min. The area under the curve (AUC) for the first 5 or 30 min was compared between groups. Ropivacaine induced a lengthening of the PR interval by 17% (P = 0.0001), His-ventricle-interval by 58% (P = 0.001), sinus QRS complex by 56% (P = 0.0001), paced QRS at 150 bpm by 257% (P = 0.0001), and at 120 bpm by 143% (P = 0.0001) in all groups. At 5 min after treatment, sinus QRS in the NaHCO₃ group was shorter than that in the CTL group (AUC_QRS5, P = 0.003) or ILE group (AUC_QRS5, P = 0.045). During the first minute, seven of the animals in the NaHCO₃ group vs. two in the ILE or 0 in the CTL group recovered more than 30% of the sinus QRS previously lengthened by ropivacaine (P = 0.003). Sodium bicarbonate reversed the electrophysiological toxicity of ropivacaine faster than ILE and control groups.     

Pharmacokinetics of a new carbapenem,DA-1131, after intravenous administration to rats with alloxan-induced diabetes mellitus

Because physiological changes occurring in diabetes patients could alter the pharmacokinetics of drugs used to treat the disease, the pharmacokinetics and tissue distribution of DA-1131, a new carbapenem antibiotic, were investigated after 1-min intravenous (iv) administration of the drug, 50 mg kg⁻¹, to control and alloxan-induced diabetes mellitus (AIDM) rats. The impaired kidney function was observed by pretreatment with alloxan based on physiological parameters of plasma, creatinine clearance, and the kidney microscopy. After 1-min iv infusion of DA-1131, the plasma concentrations of DA-1131 and the total area under the plasma concentration–time curve of DA-1131 from time zero to time infinity (AUC) increased significantly in the AIDM rats (7350 versus 4400 μg min mL⁻¹) when compared with those in control rats. This was due to significantly slower total body clearance (Cl) of DA-1131 (6.80 versus 11.4 mL min⁻¹ kg⁻¹) in AIDM rats than that in control rats. The significantly slower Cl of DA-1131 in AIDM rats was due to significantly slower renal (2.62 versus 4.95 mL min⁻¹ kg⁻¹, because of the considerably decreased glomerular filtration rate of DA-1131) and nonrenal (3.99 versus 6.34 mL min⁻¹ kg⁻¹, possibly because of the considerably slower metabolism in rat liver and kidney) clearance in AIDM rats. The amount of DA-1131 recovered from each rat tissue studied was significantly higher in AIDM rats than that in control rats, however, the tissue to plasma ratios were not significantly different between the two groups of rats. © 1998 John Wiley & Sons, Ltd.     

DOSE-INDEPENDENT PHARMACOKINETICS OF THE CARDIOPROTECTIVE AGENT DEXRAZOXANE IN DOGS

A randomized, four-way cross-over design was used to assess the disposition of the cardioprotective agent, dexrazoxane, in four male beagle dogs following single I.V. administration of 10, 25, 50, and 100 mg kg⁻¹ doses. Parent drug was quantified in plasma and urine with a validated high-pressure liquid chromatographic–electrochemical assay. A two-compartment open model adequately described the dexrazoxane plasma concentration versus time data. The terminal half-life ranged between 1·1 and 1·3 h and the apparent steady-state distribution volume was 0·67 L kg⁻¹. The systemic clearance (CL) ranged from 10.3 to 11·5 mL min⁻¹ kg⁻¹, while estimates of renal clearance approximated the glomerular filtration rate (GFR ≈3·2–4·9 mL min⁻¹ kg⁻¹). Over the dose range evaluated, CL was dose independent (ANOVA, p=0·33), while concentration at the end of infusion (C_end) and the area under the concentration versus time curve (AUC) were directly proportional to the dose (r>0·999). The blood cell to plasma partitioning ratio was ≈0·517 and drug was essentially unbound to plasma proteins (f_u≈0·95). Dexrazoxane appeared to be subject to low organ extraction, since the hepatic and renal drug extraction ratios were on the order of 0·228±0·054 and 0·184±0·024, respectively. These results suggest a relatively small drug distribution space (approximately equal to total-body water) and low tissue and plasma protein binding. In light of the low plasma protein binding and extraction ratio exhibited by dexrazoxane, metabolic capacity and renal function would appear to be the predominant variables affecting the CL of this drug. The constancy of the half-life, CL, and V_ss with increasing dose indicates dose-independent disposition for dexrazoxane. Thus a linear increase in the systemic exposure can be predicted over this dose range.     

Pharmacokinetic and pharmacodynamic changes of furosemide after intravenous and oral administration to rats with alloxan-induced diabetes mellitus

Because some physiological changes occurring in diabetes mellitus patients could alter the pharmacokinetics and pharmacodynamics of the drugs to treat the disease, the pharmacokinetics and pharmacodynamics of furosemide were investigated after intravenous (i.v.) and oral administration of the drug (6 mg per whole body weight) to control rats and alloxan-induced diabetes mellitus rats (AIDRs). After i.v. administration, the total body clearance (5.47 versus 7.05 mL min⁻¹ kg⁻¹) was significantly slower in AIDRs and this was due to significantly slower renal clearance (2.35 versus 4.33 mL min⁻¹ kg⁻¹) because the nonrenal clearance was comparable between two groups of rats. The 8 h urinary excretion of furosemide after i.v. administration decreased significantly (2280 versus 3760 μg) in AIDRs due to impaired kidney function; the glomerular filtration rate measured by creatinine clearance was significantly slower (2.86 versus 4.33 mL min⁻¹ kg⁻¹) and both the plasma urea nitrogen (43.5 versus 17.3 mg dL⁻¹) and kidney weight (0.953 versus 0.749% of body weight) increased significantly in AIDRs. This resulted in a significant decrease in the 8 h urine output per g kidney (17.8 versus 43.6 mL) in AIDRs. However, the 8 h diuretic efficiency was not significantly different between two groups of rats. After oral administration, the area under the plasma concentration–time curve from time 0 to 8 h decreased significantly in AIDRs (1200 versus 1910 μg·min mL⁻¹) due to considerably decreased absorption of furosemide from gastrointestinal tract of AIDRs. After oral administration, the 8 h urine output per g kidney (18.6 versus 36.4 mL) also decreased significantly in the AIDRs due to significantly decreased 8 h urinary excretion of furosemide (405 versus 2210 μg), however, the 8 h diuretic efficiency increased significantly (127 versus 35.2 mL mg⁻¹) in AIDRs. © 1998 John Wiley & Sons, Ltd.     

Comparing early liver graft function from heart beating and living‐donors: A pilot study aiming to identify new biomarkers of liver injury

The liver and kidney functions of recipients of liver transplantation (LT) surgery with heart beating (HBD, n  = 13) or living donors (LD, n  = 9) with different cold ischemia times were examined during the neohepatic phase for the elimination of rocuronium bromide (ROC, cleared by liver and kidney) and tranexamic acid (TXA, cleared by kidney). Solid phase micro‐extraction and LC–MS/MS was applied to determine the plasma concentrations of ROC and TXA, and creatinine was determined by standard laboratory methods. Metabolomics and the relative expressions of miR‐122, miR‐148a and γ‐glutamyltranspeptidase (GGT), liver injury biomarkers, were also measured. The ROC clearance for HBD was significantly lower than that for LD (0.147 ± 0.052 vs. 0.265 ± 0.148 ml·min⁻¹·g⁻¹ liver) after intravenous injection (0.6 mg·kg⁻¹). The clearance of TXA, a compound cleared by glomerular filtration, given as a 1 g bolus followed by infusion (10 mg·kg⁻¹·h⁻¹), was similar between HBD and LD groups (~ 1 ml·min⁻¹·kg⁻¹). The TXA clearance in both groups was lower than the GFR, showing a small extent of hepatorenal coupling. The miR‐122 and miR‐148a expressions were similar for the HBD and LD groups, whereas GGT expression was significantly increased for HBD. The lower ROC clearance and the higher GGT levels in the HBD group of longer cold ischemia times performed worse than the LD group during the neophase. Metabololmics further showed clusters of bile acids, phospholipids and lipid ω‐oxidation products for the LD and HBD groups. In conclusion, ROC CL and GGT expression, and metabolomics could serve as sensitive indices of early graft function. Copyright © 2017 John Wiley & Sons, Ltd.     

Neuromuscular blocking characteristics of vecuronium after tubocurarine-induced “fade”An experimental double-blind clinical study

Objective: The fade in train-of-four (TOF) monitoring is considered to be due to blocking of the prejunctional nicotinic acetylcholine receptors (AchRs). During onset of the neuromuscular block (NMB) tubocurarine (TC) causes more fade in the TOF responses than vecuronium (VEC). Therefore we wanted to investigate whether onset or duration of action of VEC or TC would be improved with a priming dose of an agent with different prejunctional activity. Methods: The rates of NMB were measured following priming doses of 0.15 mg · kg⁻¹ of TC and 0.015 mg ·  kg⁻¹ of VEC with 6 min priming time. The individual time course of action of 0.6 mg · kg⁻¹ of TC (1.13 × ED 95) and 0.1−0.2 mg · kg⁻¹ of VEC (1.75–3.5 × ED95) were examined with a priming dose of the same agent or the other agent, by measurement of changes in the evoked compound EMG from the hypothenar muscle. Results: Priming doses of TC decreased mean TOF ratio to 67% [95% confidence interval (CI) = 56–78] during priming time, which was significantly lower than after priming with VEC 87% (76–97; P < 0.001). Despite the higher TOF ratio, the priming dose of VEC accelerated the onset time of intubation dose of TC more than the priming dose of TC (P = 0.0018). Priming with TC prolonged the duration of VEC-induced NMB by 35–70 min compared with priming with VEC, which means that a small priming dose of TC changes VEC from a muscle relaxant with intermediate action to a long-acting agent. Conclusion: Priming with TC caused a lower TOF ratio; however, priming with TC did not accelerate the onset time of either agent as much as priming with VEC. It appears that potentiation of NMB after combination of VEC and TC is not dependent on “fade” receptors. Received: 17 August 1998 / Accepted in revised form: 14 December 1998     

THE EFFECT OF INTRAVENOUS INFUSION TIME ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF THE SAME TOTAL DOSE OF AZOSEMIDE IN RABBITS

The pharmacokinetics and pharmacodynamics of azosemide were evaluated after intravenous (IV) administration of the same total dose of azosemide, 1 mg kg⁻¹, in different infusion times, 1 min (treatment I) and 4 h (treatment II) to rabbits (n =5, each). The loss of water and electrolytes in urine induced by azosemide was immediately replaced with infusion of equal volume of lactated Ringer's solution. Some pharmacokinetic parameters of azosemide were different between treatments I and II. For example, the mean value of terminal half-life (70·5 versus 107 min), total body clearance (5·88 versus 8·32 mL min⁻¹ kg⁻¹), renal clearance (3·45 versus 6·51 mL min⁻¹ kg⁻¹), and mean residence time (18·5 versus 31·7 min) increased significantly in treatment II. The 8 h urine output (236 versus 733 mL) and 8 h urinary excretion of sodium (29·2 versus 76·4 mmol) and chloride (27·5 versus 78·9 mmol) increased significantly in treatment II although the total amount of 8 h urinary excretion of unchanged azosemide increased by only 15% in treatment II. This could be due to the fact that the urinary excretion rates of azosemide in treatment II remained for a longer period of time close to the maximally efficient urinary excretion rates of azosemide for both urine output and urinary excretion rates of sodium than in treatment I. Plasma concentrations of azosemide and hourly urine output and hourly urinary excretion of azosemide, sodium, potassium, and chloride during the apparent steady state (between 2 and 4 h) in treatment II were fairly constant. © 1997 by John Wiley & Sons, Ltd.     

Pharmacokinetics and haemodynamic effect of deacetyl diltiazem (M1) in rabbits after a single intravenous administration

Deacetyl diltiazem (M₁) is a major metabolite of the widely used calcium antagonist diltiazem (DTZ). In order to study the pharmacokinetic and haemodynamic effects of this metabolite, M₁ was administered as a single 5 mg kg⁻¹ dose intravenously (iv) to New Zealand white rabbits (n = 5) via a marginal ear vein. Blood samples, blood pressure (SBP and DBP), and heart rate (HR) recordings were obtained from each rabbit up to 8 h, and urine samples for 48 h post-dose. Plasma concentrations of M₁ and its metabolites were determined by HPLC. The results showed that the only quantifiable basic metabolite in the plasma was deacetyl N-monodesmethyl DTZ (M₂). The t_1/2 and AUC of M₁ and M₂ were 2.1±0.5 and 3.0±1.1 h, and 1300±200 and 240±37 ng h mL⁻¹, respectively. The Cl and Cl_r of M₁ were 60±10 and 0.81±0.63 mL min⁻¹ kg⁻¹, respectively. M₁ significantly decreased blood pressure (SBP and DBP) for up to 1 h post-dose (p <0.05), but had no significant effect on the heart rate (p >0.05). The E_max and EC₅₀ as estimated by the inhibitory sigmoidal E_max model were 20±18% 620±310 ng mL⁻¹, respectively for SBP; 20±8.3% and 420±160 ng mL⁻¹ for DBP. © 1998 John Wiley & Sons, Ltd.     

PHARMACOKINETICS OF THE ENANTIOMERS OF VERAPAMIL AFTER INTRAVENOUS AND ORAL ADMINISTRATION OF RACEMIC VERAPAMIL IN A RAT MODEL

Verapamil is a chiral calcium channel blocking drug which is useful clinically as the racemate in treating hypertension and arrhythmia. The published pharmacokinetic data for verapamil enantiomers in the rat model are limited. Utilizing a stereospecific high-performance liquid chromatographic (HPLC) assay, the enantiomeric disposition of verapamil is reported after intravenous (1·0 mg kg⁻¹) and oral (10 mg kg⁻¹) administration of racemic verapamil to the rat model. After intravenous administration the systemic clearance of R-verapamil was significantly greater than that of S-verapamil; 34·9 ± 7 against 2·7 ± 3·7 mL min⁻¹ kg⁻¹ (mean ± SD), respectively. After oral administration, the clearance of R-verapamil was significantly greater than that of S-verapamil, 889 ± 294 against 351 ± 109 mL min⁻¹ kg⁻¹, respectively. The apparent oral bioavailability of S-verapamil was greater than that of R-verapamil, 0·074 ± 0·031 against 0·041 ± 0·011, respectively. These data suggest that the disposition of verapamil in the rat is stereoselective; verapamil undergoes extensive stereoselective first-pass clearance after oral administration and the direction of stereoselectivity in plasma is opposite to that observed in the human. © 1997 John Wiley & Sons, Ltd.