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.     

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.     

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.     

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.     

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.     

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.     

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.     

A PHARMACOKINETIC STUDY WITH THE HIGH-DOSE ANTICANCER AGENT MENADIONE IN RABBITS

The aim of this investigation was to assess the pharmacokinetic properties of high-dose menadione (VK₃), as an anticancer agent, in plasma and red blood cells (RBCs) in rabbits. An extremely high dose of 75 mg menadiol sodium diphosphate (Synkayvite) was intravenously injected. HPLC analysis was applied to measure the major metabolite, menadione, VK₃. The kinetic properties of VK₃ in both plasma and red blood cells showed a short elimination half-life, high clearance, and large volume of distribution in plasma and RBCs. The mean elimination t_1/2 values of menadione in plasma and in RBCs were 27·17±10·49 min and 35·22±11·82 min, respectively. The plasma clearance (CL/F) of VK₃ was 0·822±0·254 L min⁻¹. The systemic clearance in RBCs was 0·407±0·152 L min⁻¹. The apparent volume of distribution (V_d/F) in plasma was 30·833±12·835 L and that in RBCs 20·488±9·401 L. The plasma AUC was 32·453±9·785 μg min mL⁻¹ and that of RBCs 67·219±24·449 μg min mL⁻¹. Menadiol was rapidly biotransformed to menadione in blood. The formation rate constant (k_f) of menadione in plasma was 0·589±0·246 min⁻¹, and that of RBCs 1·520±1·345 min⁻¹. Through this study the estimated menadione dosage needed to maintain a plasma level of 1 μg mL⁻¹ for anticancer purposes was 19·7 mg kg⁻¹ every hour.     

Quinine impairs quinidine clearance in rat perfused liver

Abstract— We have examined the disposition of the cinchona alkaloids quinine and quinidine in the rat recirculating isolated perfused liver preparation. When administered as separate 1 mg doses, the hepatic clearances of quinine and quinidine were similar to the hepatic perfusate rate of 10 mL min^?1. When 1 mg of each was administered simultaneously, mean hepatic clearance of quinine was unchanged (9·00 ± 2·20 mL min^?1 separate dosage, n = 7; 6·87 ± 1·77 mL min^?1 simultaneous dosage, n = 7; P > 0·05). By contrast, mean hepatic clearance of quinidine was reduced significantly by concomitant quinine (10·6 ± 1·72 mL min^?1 separate dosage, n = 7; 4·82 ± 1·25 mL min^?1 simultaneous dosage, n = 7; P < 0·05). There was no significant difference in volumes of distribution when each alkaloid was administered separately (131 ± 46 mL quinine, 129 ± 21 mL quinidine; P > 0·05) but concomitant quinine administration increased quinidine volume of distribution to 169 ± 30 mL (P < 0·05). Four further experiments with simultaneous dosages of 0·5 mg of each alkaloid produced similar findings, indicating that the interactions did not derive from nonlinear drug disposition.     

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.     

Pharmacokinetics of a new reversible proton pump inhibitor,YH1885, after intravenous and oral administrations to rats and dogs: hepatic first-pass effect in rats

The pharmacokinetics of YH1885 were evaluated after intravenous (iv) and oral administrations of the drug to rats and dogs. The reason for the low extent of bioavailability (F) of YH1885 after oral administration of the drug to rats and the absorption of the drug from various rat gastrointestinal (GI) segments were also investigated. After iv administration of YH1885, 5–20 mg kg⁻¹, to rats, the pharmacokinetic parameters of YH1885 seem to be independent of the drug at the dose ranges studied. After oral administration of YH1885, 50–200 mg kg⁻¹, to rats, the area under the plasma concentration–time curve from time zero to 12 or 24 h (AUC_{0–12 h} or AUC_{0–24 h}) was proportional to the oral dose of the drug, 50–100 mg kg⁻¹, however, the AUC_{0–24 h} value at 200 mg kg⁻¹ increased with less proportion to the dose increase (324, 689, and 815 μg · min mL⁻¹ for 50, 100, and 200 mg kg⁻¹, respectively) due to the poor water solubility of the drug. This was proved by the considerable increase in the percentages of the oral dose remaining in the entire GI tract as unchanged YH1885 at 24 h (11.8, 15.3, and 42.8% for 50, 100, and 200 mg kg⁻¹, respectively). The F value after oral administration of YH1885 to rats was relatively low; the value was approximately 40% at the oral dose of 50 and 100 mg kg⁻¹. The reason for the low F in rats was investigated. The liver showed the highest metabolic activity for YH1885 based on an in vitro rat tissue homogenate study; hence, the liver first-pass effect was estimated. The value of AUC after intraportal administration of the drug, 5 mg kg⁻¹, was approximately 70% (116 versus 163 μg · min mL⁻¹) of that after iv administration of the drug, 5 mg kg⁻¹, to rats; the liver first-pass effect of YH1885 in rats was estimated to be approximately 30%. The total body clearance of YH1885 after iv administration of the drug, 5–20 mg kg⁻¹, to rats were considerably lower than the cardiac output of rats, indicating that the lung and/or heart first-pass effect of YH1885 could be negligible in rats. After oral administration of YH1885, 50 and 100 mg kg⁻¹, to rats, the F value was approximately 40%, and approximately 15% of the oral dose was recovered from the entire GI tract as unchanged YH1885 at 24 h, and 30% of the oral dose disappeared with the liver first-pass effect. Therefore, the remainder, approximately 15% of the oral dose, could have disappeared with the small intestine first-pass effect and/or degradation of the drug in the GI tract. YH1885 was absorbed from ileum, duodenum, and jejunum of rat, however, YH1885 was under the detection limit in plasma when the drug was instilled into the rat stomach and large intestine. After iv administration of YH1885, 5–20 mg kg⁻¹, to dogs, the pharmacokinetic parameters of YH1885 also seemed to be independent of the drug at the dose ranges studied. However, after oral administration of YH1885, 0.5 and 2 g per whole body weight, to dogs, the AUC_{0–10 h} values were not significantly different (96.8 versus 98.2 μg · min mL⁻¹) and this could be due to the poor water-solubility of the drug. YH1885 was not detected in the urine after both iv and oral administration of the drug to both rats and dogs. Copyright © 1998 John Wiley & Sons, Ltd.     

THE PHARMACOKINETICS OF 1954U89, 1, 3-DIAMINO-7-(1-ETHYLPROPYL)-8-METHYL-7H-PYRROLO-(3, 2-f )QUINAZOLINE,IN DOGS AND RATS AFTER INTRAVENOUS AND ORAL ADMINISTRATION

1954U89, 1, 3-diamino-7-(1-ethylpropyl)-8-methyl-7H-pyrrolo-(3, 2-f )quinazoline, is a potent, lipid-soluble inhibitor of dihydrofolate reductase. The pharmacokinetics and bioavailability of 1954U89 were examined in male beagle dogs and male CD rats. Dogs received single intravenous (2·5 mg kg⁻¹) and oral (5·0 mg kg⁻¹) doses of 1954U89 with and without successive administration of calcium leucovorin. Single intravenous (5·0 mg kg⁻¹) and oral (10 mg kg⁻¹) doses of [1,3-¹⁴C₂]1954U89 were administered to rats. Plasma concentrations of total radiocarbon were determined by scintillation counting, and intact 1954U89 was measured by HPLC. The mean plasma half-life was 3·2 ± 0·62 and 4·2 ± 0·68 h after intravenous and oral administration, respectively, to dogs. The pooled plasma half-life after intravenous administration to rats averaged 1·2 h; a reliable plasma half-life value after oral administration could not be determined. Mean total-body clearance was 2·4 ± 0·39 and 4·5 ± 1·1 L h⁻¹ kg⁻¹ after intravenous and oral administration, respectively, to dogs, and averaged 12 and 77 L h⁻¹ kg⁻¹ after intravenous and oral administration, respectively, to rats. Neither clearance nor bioavailability of 1954U89 in dogs was affected significantly by administration of calcium leucovorin. Absolute bioavailability was 54 ± 12% in dogs and 16% in rats. © 1997 John Wiley & Sons, Ltd.     

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.     

A dose-dependent pharmacokinetic study on caffeic acid in rabbits after intravenous administration

The dose-dependent pharmacokinetics of caffeic acid (CA) were studied in rabbits. Three different doses (5, 10, and 25 mg kg⁻¹) were administered intravenously to six rabbits each. The concentration–time profiles for CA could be fitted by a two-compartment model for each dose. The results showed that total-body clearance and elimination rate constant from the central compartment (k₁₀) after a 5 mg kg⁻¹ dose were greater than those after the other two doses. Furthermore, the terminal elimination half-life (β half-life) and mean residence time (MRT) after a 5 mg kg⁻¹ dose were less than after the other doses. The AUC value increased linearly with dose within the range of 10–25 mg kg⁻¹. Most of the unchanged caffeic acid was excreted in the urine within 2 h. The percentage of unchanged caffeic acid excreted in the urine was 63·4, 60·0, and 55·4% after doses of 5, 10, and 25 mg kg⁻¹, respectively, which was not significantly different. However, significant differences in the renal clearances and renal excretion rate constants were observed with a 5 mg kg⁻¹ dose compared to the other doses. On the other hand, nonrenal clearances and nonrenal excretion rate constants showed no dose-related differences. The differences observed in total-body clearance, k₁₀, β half-life, and MRT between a 5 mg kg⁻¹ dose and the other doses can be explained on the basis of the differences in renal clearance and renal excretion rate constants. ©1997 John Wiley & Sons, Ltd.     

Influence of intravenous infusion of ethanol on regional blood flow in conscious rats

Abstract— The effects of intravenous infusions of ethanol and saline (0·9% NaCl) on mean arterial pressure (MAP), heart rate (HR), total peripheral resistance (TPR), cardiac contractility (dP/dt_max) and systemic haemodynamics were studied in conscious, unrestrained rats by the radioactive microsphere technique. Saline (0·03 and 0·06 mL min^?1 kg^?1 for 12 min each dose) in the time-control group did not affect MAP, HR, TPR, dP/dt_max or vascular conductances in any organs or beds. While the low dose ethanol (2·4 mg min^?1 kg^?1) did not alter MAP, HR, TPR, systemic haemodynamics or dP/dt_max, the high dose (4·8 mg min^?1 kg^?1) slightly reduced MAP and TPR but did not affect HR, cardiac output or dP/dt_max. Both doses of ethanol vasodilated the intestine and spleen, but vasoconstricted the skin. The high dose caused additional vasodilatation in the heart and testes and the low dose also constricted the skeletal muscle bed. Our results show that ethanol, at non-hypotensive or slightly hypotensive doses, has marked vasodilator effects in the heart, intestine, spleen and testes.     

Effects of Hyperlipidemia on the Pharmacokinetics of Nifedipine in the Rat

Purpose. The effect of hyperlipidemia on nifedipine pharmacokinetics was studied. The mechanisms by which hyperlipidemia affects pharmacokinetics of drugs are mainly undetermined. Hyperlipidemia may decrease the fraction of unbound drug in plasma and/or decrease intrinsic ability of the cytochrome P-450 systems due to excess membrane cholesterol. Hyperlipidemia is a primary risk factor for coronary artery disease leading to hypertension and ischemic heart disease, for which nifedipine, a calcium channel blocker, is used. Methods. Poloxamer 407 (P407)-induced hyperlipidemic rat model was used to study the effects of hyperlipidemia on the pharmacokinetics of nifedipine (6 mg kg^–1 given iv, ip and po). Total plasma cholesterol levels increased from 0.82–2.02 to 5.27–11.05 mmol L^–1 48 h post P407 administration (Ig kg^–1, ip). Protein binding studies were conducted by an ultrafiltration method. Results. Hyperlipidemia significantly decreased CL_TB by 38% and CL_TB/F by 45 and 42% following po and ip doses, respectively, thereby increasing AUC_0–, C_max and half-life. Absolute bioavailability and Vd_ss remained unchanged. AUC_0– was affected to the same extent in each route of administration, therefore, the effect was mainly systemic rather than presystemic. Hyperlipidemia significantly lowered the fraction unbound in plasma by approximately 31%. Conclusions. The altered pharmacokinetics of nifedipine by P407-induced HYPERLIPIDEMIA may be, at least in part, due to the decrease in fraction unbound in plasma. A decrease in intrinsic clearance, however, cannot be ruled out.     

Influence of Age on the Disposition and Renal Handling of Enprofylline in Rats

Abstract— The effects of ageing on the pharmacokinetics, renal handling and protein binding of enprofylline were investigated in 6-, 13- and 18-month-old male Fischer 344 rats. Concentrations of enprofylline in plasma and urine were determined by HPLC, and pharmacokinetic parameters were estimated by model-independent methods. No significant differences in the volume of distribution, systemic clearance of enprofylline or urinary recovery of unchanged enprofylline (> 85%) were observed among any of the groups of rats. The dissociation constant and free fatty acid concentration in plasma increased with age. Age-dependent decreases in the systemic clearance for unbound drug were observed, and the volume of distribution for unbound drug tended to decrease with age. The ratio of systemic clearance for unbound drug to the glomerular filtration rate (GFR) decreased with ageing. Ageing was associated with decreases in the apparent maximum capacity of transport (V_max) (223·33,160·24 and 142·98 μg min^?1 kg^?1 for 6-, 13- and 18-month-old rats, respectively) and in the tubular secretory intrinsic clearance (V_max/K_m) of enprofylline (75·45, 51·03 and 44·13 mL min^?1 kg^?1, respectively), while a slight change in the Michaelis-Menten constant (K_m) was observed. These results indicate that the mechanism responsible for age-related changes in the disposition and renal handling of enprofylline may be responsible for a decrease in the ability of the tubular anion transport system.