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.     

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.     

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.     

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.     

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.     

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.     

GLUCURONIDATION OF DIFLUNISAL, (−)-MORPHINE, 4-NITROPHENOL,AND PROPOFOL IN LIVER MICROSOMES OF TWO PATIENTS WITH CRIGLER–NAJJAR SYNDROME TYPE I

In vitro glucuronidation was studied in liver microsomes from two patients with Crigler–Najjar type I (CN-I) disease and compared with the activity measured in microsomes prepared from six control human livers. The UDP-glucuronosyltransferase (UGT) activity was determined toward the following substrates: 4-nitrophenol, propofol, (−)-morphine (formation of the 3-glucuronide), and diflunisal (formation of the phenolic and acyl glucuronides). Glucuronidation of 4-nitrophenol was reduced in one of the CN-I livers (CN-I No. 1) (0·9 nmol min⁻¹ mg⁻¹) and normal in the other CN-I liver (CN-I No. 2) (3.5 nmol min⁻¹ mg⁻¹) compared to the control livers (5·6±2·9 nmol min⁻¹ mg⁻¹, mean±S.D.). Propofol glucuronidation was not detectable (i.e. less than 0·100 nmol min⁻¹ mg⁻¹) in the CN-I No. 1 liver and normal in the CN-I No. 2 liver (1·78 nmol min⁻¹ mg⁻¹ against 1·52±0·72 nmol min⁻¹ mg⁻¹ in the control livers). The glucuronidation of (−)-morphine to the 3-glucuronide and the formation of the phenolic and acyl glucuronides of diflunisal were normal in both CN-I livers compared to the control livers. Our results show that CN-I patients are heterogeneous regarding UGT activity toward the phenolic substances 4-nitrophenol and propofol.     

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 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.     

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.     

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.     

The Protective Effect of Glycine in Cisplatin Nephrotoxicity: Inhibition with NG-Nitro-l-arginine Methyl Ester

Abstract— The effect of glycine on the acute changes in renal haemodynamics and nephrotoxicity produced by cisplatin was investigated in the rat. Cisplatin (6·0 mg kg^?1, i.v.) injection in anaesthetized rats produced, over a period of 2 h, falls of approximately 50% in renal blood flow (RBF) and the clearance of [³H]inulin (CL_IN), effects which were prevented by co-administration of glycine (1·0 g kg^?1). Infusion of the nitric oxide (NO) synthase-inhibitor N^G-nitro-l -arginine methyl ester, l -NAME (10 μg min^?1 kg^?1, i.v.), abolished glycine's ability to maintain RBF in cisplatin-injected rats whilst partially inhibiting the ability of glycine to preserve CL_IN. Treatment of cisplatin-injected rats with glycine (1·0 g kg^?1, i.v.) significantly ameliorated the nephrotoxic effects of cisplatin (6·0 mg kg^?1) as judged by improvements in a range of indices of renal function which included plasma urea and creatinine concentrations, urine output, sodium excretion, CL_IN and the clearance of [¹⁴C]p-aminohippurate. Administration of l -NAME (1·0 mg kg^?1, i.v.) to rats which received cisplatin and glycine significantly inhibited the reno-protective effect of glycine. However, l -NAME administration to rats which were treated only with cisplatin did not result in any potentiation of cisplatin nephrotoxicity. The findings of this study suggest that glycine can block the acute falls in RBF and C_IN produced by cisplatin by a mechanism which involves the production of NO. Furthermore, the results indicate that these renal haemodynamic actions of glycine are responsible, at least in part, for the ability of this amino acid to ameliorate cisplatin nephrotoxicity.     

Plasma pharmacokinetics and urinary and biliary excretion of a new potent tripeptide HIV-1 protease inhibitor,KNI-272, in rats after intravenous administration

The pharmacokinetic (PK) characteristics of KNI-272, a potent and selective HIV-1 protease inhibitor, were evaluated in rats after intravenous (IV) administration. The effect of dose on KNI-272 plasma kinetics, and the urinary and biliary elimination kinetics of KNI-272, were examined. After IV administration of 10.0 mg kg^?1 KNI-272, the mean terminal elimination half-life, t_1/2λz, was 3.49 ± 0.19 (SE) h, the total plasma clearance, CL_tot, was 15.1 ± 1.2 mL min^?1 and the distribution volume at steady state, V_d,ss, was 3790±280 mL kg^?1. On the other hand, after 1.0mg kg^?1 IV administration, t_d,ss, was 3.04±0.11 h, CL_tot was 15.9±0.2mL min^?1, and V_d,ss was 6950±600 mL kg^?1. The PK parameters of KNI-272 after IV administration showed that the disposition of KNI-272 in the rat plasma is linear within the dose range from 1.0 to 10.0mg kg^?1. Using an equilibrium dialysis method, the plasma binding of KNI-272 was measured in vitro. The free fractions were 17.7 ± 0.6%, 12.1±1.5%, and 13.8 ± 1.4% at the total concentration ranges of 9.898 ± 0.097 μg mL^?1, 0.888 ± 0.008 μg mL^?1, and 0.470±0.55 μg mL^?1, respectively. The percentages of the dose excreted into the urine and bile as the unchanged form were 1.20 ± 1.06% and 1.61 ± 0.32% at 1.0mg kg^?1 dose, and 0.164 ± 0.083% and 1.42 ± 0.26% at 10.0 mg kg^?1 dose, respectively. The renal clearance (CL_R) and the biliary clearance (CL_B) were calculated to be 0.191 and 0.256mL min^?1 for 1.0mg kg^?1, and 0.0248 and 0.215 mL min^?1 for 10.0 mg kg^?1, respectively. When comparing these values with the CL_tot values, the urinary and biliary excretion of KNI-272 are minor disposition routes.     

PHARMACOKINETICS AND ABSOLUTE BIOAVAILABILITY OF EPRISTERIDE IN HEALTHY MALE SUBJECTS

The objective of the current investigation was to describe the pharmacokinetics and absolute oral bioavailability of epristeride. Twelve healthy male subjects (mean (SD) age, 27 (6·2) years) received a single oral dose of 5 mg and an intravenous infusion of 4·5 mg over 30 min in a crossover fashion. Blood samples were obtained over 72 h for the determination of epristeride plasma concentrations using a sensitive high-performance liquid chromatography assay. The lower limit of quantification was 5 ng mL⁻¹. Pharmacokinetic analysis of the plasma concentration--time data was performed by both non-compartmental and compartmental methods. Absolute bioavailability was determined using dose-normalized AUC values following oral and intravenous administration. Epristeride plasma concentrations declined in a biexponential fashion with secondary peaks evident around 24 h in a majority of subjects following both routes of administration. Maximal plasma concentrations were typically achieved approximately 4 h after oral dosing. The mean apparent terminal elimination half-life estimates were similar following intravenous and oral administration and were 27·3 and 26·2 h, respectively. The mean plasma clearance and steady-state volume of distribution were 0·33 (0·09) mL min⁻¹ kg⁻¹ and 0·54 (0·17) L kg⁻¹, respectively. The mean absolute bioavailability was 93% (95% CI: 84%, 104%). Following compartmental analysis of the intravenous data, the mean (SD) λ₁ and λ₂ half-life estimates were 2·74 (0·48) and 31·8 (19·5) h, respectively. The % AUC associated with the λ₂ exponential phase was approximately 68%. This long half-life allows for once-daily dosing of epristeride.     

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.     

PHARMACOKINETICS OF HIGENAMINE IN RABBITS

The pharmacokinetics of higenamine were investigated in rabbits by IV bolus, PO route, and IV infusion. Plasma higenamine concentration declined rapidly in a biexponential pattern, with a terminal half-life of 22 min. The AUC increased proportionally with increasing dose, whereas the percentage of unchanged higenamine excreted from urine remained constant when dose was increased. The means of total body clearance, mean residence time, volume of distribution at steady state, and fraction of urinary excretion were 127·7 mL min⁻¹ kg⁻¹, 9·28 min, 1·44 L kg⁻¹, and 5·48%, respectively. The mean percentage of protein binding of higenamine in plasma was 54·8% at steady state after IV infusion. The results from post-infusion also confirmed that higenamine followed a two-compartment open model in animals. After oral administration, higenamine was rapidly absorbed to reach peak concentration within 10 min. Interestingly, the plasma concentration–time profiles revealed two distinguishable groups with different C_max, extent of absorption, and urinary excretion. The average absolute bioavailabilities of higenamine calculated by AUCs and accumulated urinary excretion were 21·86 and 2·84% versus 20·19 and 5·50% for the two groups, respectively. Upon hydrolysis of urine samples with μ-glucuronidase, urinary concentrations of higenamine were greatly enhanced in both groups     

Dose Regimen Adjustment for Milrinone in Congestive Heart Failure Patients with Moderate and Severe Renal Failure

This study was designed to test a proposed dose modification for intravenous milrinone in congestive heart failure patients (CHF, NYHA I-II) with either moderate or severe renal impairment. All the patients were administered an intravenous loading dose of drug at 50 μg kg-1 over 10 min. This was followed by an 18 h maintenance infusion of milrinone at 0·45 or 0·35 μg kg^?1 min^?1 for the moderate (chromium-EDTA clearance of 31–75 mL min^?1, n = 10) and severe renally impaired subjects (chromium-EDTA of clearance 10–30 mL min^?1, n = 11), respectively. Plasma and urine samples were collected for up to 34 h and analysed for parent drug by validated HPLC methods. The mean (± s.d.) steady-state plasma concentrations of milrinone were within the therapeutic range (100–300 ng mL^?1) for both groups, with values of 239 ± 71 ng mL^?1 and 269 ± 32 ng mL^?1 for the moderate and severe patients, respectively. No statistical differences were observed between the steady-state values for the two groups. With the exception of two patients per group, individual steady-state levels were also within the therapeutic range. Those outside the nominal range showed steady-state levels, ranging between 308 and 353 ng mL^?1, that were not associated with any serious adverse events. As predicted for this highly renally cleared drug, there were differences (P < 0·001) in the total plasma clearance (CL_P), renal clearance (CL_r), and plasma terminal half-life (t1/2) of drug, with values in the severe group being 44% lower, 75% lower, and about 134% longer respectively, when compared with the moderate group. High (correlation coefficient > 0·8) and significant correlations (P < 0·001) were observed between CL_P and CL_r and the degree of renal impairment (chromium-EDTA clearance). The apparent volume of distribution was approximately 40% higher (P < 0·01) in the severe group compared with that for the moderate group (moderates were 0·443 ± 0·155 L kg^?1). This volume difference suggests a decrease in the plasma protein-binding of milrinone because of the renal disease. The fraction of drug excreted in the urine was 0·705 ± 0·100 for the moderate group and 0·320 ± 0·089 for the severe group (P < 0·001). These results may suggest an increase in non-renal clearance of the compound, representing a partial compensation mechanism for the reduced renal function. In conclusion, this study has confirmed that the current dose reductions recommended for the use of intravenous milrinone in CHF patients with impaired renal function will yield plasma concentrations of the drug within the therapeutic range.     

COMPARISON OF PHARMACOKINETICS OF M1, M2, M3, AND M4 AFTER INTRAVENOUS ADMINISTRATION OF DA-125 OR ME2303 TO MICE AND RATS. NEW ADRIAMYCIN ANALOGUES CONTAINING FLUORINE

The pharmacokinetics of M1, M2, M3, and/or M4 were compared after intravenous (iv) administration of DA-125 and/or ME2303 to mice (25 mg kg⁻¹) and rats (5, 10, 20, 30, and 40 mg kg⁻¹). The mean plasma concentrations of M1 were detected up to 8 h after iv administration of both DA-125 and ME2303 to mice, and were significantly higher for DA-125 than ME2303; this resulted in a considerably greater AUC (303 against 148 μg min mL⁻¹) and a considerably slower CL of M1 (69·3 against 136 mL min⁻¹ kg⁻¹) after iv administration of DA-125. The MRT (371 against 189 min) and CL_NR of M1 (68·7 against 136 mL min⁻¹ kg⁻¹) were considerably greater and slower, respectively, after iv administration of DA-125. The mean plasma concentrations of M2 were detected up to 8 and 4 h after iv administration of DA-125 and ME2303, respectively, to mice and were significantly higher for DA-125 than ME2303, resulting in a considerably greater AUC of M2 (148 against 27·1 μg min mL⁻¹) after iv administration of DA-125. The mean plasma concentrations of M3, being the lowest among M1–M4, were detected only up to 15 min after iv administration of both DA-125 and ME2303 to mice, and were comparable after iv adminstration of DA-125 and ME2303 to mice. The mean plasma concentrations of M4 were detected up to 8 h after iv administration of both DA-125 and ME2303 to mice, and were higher after iv administration of DA-125 than ME2303, resulting in a considerably greater AUC of M4 (197 against 61·9 μg min mL⁻¹) after iv administration of DA-125. Similar results on M1 and M2 were also obtained from rats: the mean plasma concentrations of both M1 and M2 were significantly higher after iv administration of DA-125, 10 mg kg⁻¹, than after ME2303. The plasma concentrations of M1, M2, and M4, and hence their AUCs, were significantly higher after iv administration of DA-125, 5, 10, 20, 30, and 40 mg kg⁻¹, to rats than after ME2303: the mean plasma concentrations of M2, approximately 0·1–0·4 μg mL⁻¹, were maintained from 30 min to 8–10 h after iv administration of DA-125, 20, 30, and 40 mg kg⁻¹, to rats; the plasma concentrations of M3 were the lowest among M1–M4 at all DA-125 doses; and those of M1 and M4 were maintained for a long period of time. However, after iv administration of M2, 5 mg kg⁻¹, to rats, the mean plasma concentrations of M2 were detected up to 60 min with a mean terminal half-life of only 38·8 min, and the concentrations of M3 were negligible. After iv administration of M3, 5 mg kg⁻¹, to rats, the mean plasma concentrations of M3 were detected up to 15 min; the plasma concentrations of M4, reaching their peak at 5 min, decayed more slowly and were higher than those of M3. The AUC of M4 after iv administration of M3, 5 mg kg⁻¹, was comparable to that after iv administration of M4, 5 mg kg⁻¹, to rats, suggesting that M4 is formed fast and almost completely from M3. M1 was not detected in plasma after iv administration of either M2 or M3 to rats. After iv administration of M4, 5 mg kg⁻¹, to rats, the mean plasma concentrations of M4 decayed fast with a mean terminal half-life of 43·9 min and neither M2 nor M3 were detected in plasma. The following disposition mechanisms for M1, M2, M3, and M4 after iv administration of DA-125 to rats could be obtained from the above data: (i) the maintenance of plasma concentrations of M2 for a longer period of time after iv administration of DA-125 than those after iv administration of M2 could be due to the continuous formation of M2 from M1; (ii) the lowest plasma concentrations of M3 among M1–M4 after iv administration of DA-125 could be due to the fast and almost complete formation of M4 from M3 as soon as M3 is formed from M1, and not due to the fast renal excretion of unchanged M3; (iii) M4 was exclusively and continuously formed from M3 and the formation of M4 from M2 was negligible; and (iv) reversible metabolism among M1–M4 did not take place. The following results could also be obtained after iv administration of DA-125 or ME2303 to mice and rats: (i) the lower plasma concentrations of M1 after iv administration of ME2303 than of DA-125 could be due to the greater biliary excretion of unchanged ME2303 (approximately 30% of iv dose) than unchanged DA-125 and (ii) the lower plasma concentrations of M2 and M4 after iv administration of ME2303 than after DA-125 could be due to lower plasma concentrations of M1 and hence less formation of both M2 and M4 from M1. Liver showed the highest metabolic activity for M1 and a considerable amount of M1 was also metabolized in the kidney after 30 min incubation of 50 μg of DA-125 in 9000 g supernatant fraction of rat tissue homogenates. The mean amount of M1 remaining per gram of tissue, the total amount of M1 remaining in whole tissue, and the tissue to plasma ratio of M1 were significantly higher in the heart, lung, large intestine, and kidney at 15 min after iv administration of DA-125, 25 mg kg⁻¹, to mice than after ME2303. M1, the active antineoplastic moiety of DA-125, had higher affinity for the lung after iv administration of DA-125 to mice than after ME2303, indicating that lung tumours could be subjected to a greater exposure to M1 after iv administration of DA-125 than ME2303. The 24 h biliary excretion of M1 was significantly greater after the iv administration of ME2303 than after DA-125 (344 against 79·3 μg). However, reversed results were obtained for M2 (267 against 467 μg). M3 and M4 were under the detection limit in the bile sample after iv administration of either DA-125 or ME2303.     

Pharmacokinetics of methotrexate after intravenous and intramuscular injection of methotrexate-bearing positively charged liposomes to rats

The pharmacokinetics and tissue distribution of methotrexate (MTX) were investigated after intravenous (IV) and intramuscular (IM) injection of free MTX (treatment I), freshly prepared MTX-bearing positively charged liposomes (large unilamellar vesicles), PLUVs (treatment II), and empty PLUVs mixed manually with free MTX (treatment III), 4 mg kg^?1 as free MTX to rats, using HPLC assay. After 1 min IV infusion, the plasma concentrations of MTX (C_p), the area under the plasma concentration—time curve (AUC, 173 against 314 μg mL min^?1), the terminal half-life (t_1/2, 24.0 against 412 min), the mean residence time (MRT, 13.0 against 324 min), and the apparent volume of distribution at steady state (V_SS, 289 against 3370 mL kg^?1) were significantly larger, but the total body clearance (CL, 23.1 against 12.8 mL min^?1 kg^?1), the renal clearance (CL_R, 8.38 against 3.09 mL min^?1 kg^?1), the non-renal clearance (CL_NR, 14.6 against 9.56 mL min^?1 kg^?1), and the amount of MTX excreted in urine (X_u, 415 against 275 μg) were significantly lower in treatment II than in treatment I. This could be due to the fact that some of the MTX-bearing PLUVs were entrapped in tissues and the rest were present in plasma (larger MRT and V_ss in treatment II), and MTX is slowly released from MTX-bearing PLUVs (longer t_1/2 in treatment II). In the present HPLC assay, the concentrations of MTX represent the sum of free MTX and MTX in MTX-bearing PLUVs (larger C_p and AUC and slower CL in treatment II). Saturable formation of 7-hydroxymethotrexate from MTX was reported in rabbit blood and non-linear disposition of MTX was also reported in rats and rabbits (lower X_u and CL_R in treatment II). After 1 min IV infusion, some pharmacokinetic parameters of MTX, such as AUC, CL, CL_R, CL_NR, and X_u, were significantly different between treatments I and III, but nonetheless the differences were smaller than those between treatments I and II. After both IV and IM administration, the amount of MTX remaining per gram of tissue or organ in the kidney, stomach, small intestine, and large intestine was significantly smaller in treatment II than in treatment I. Such tissue results imply that the side-effects of MTX on kidney and GI tract could be reduced after both IV and IM administration of MTX-bearing PLUVs rather than free MTX. The encapsulation efficiency of MTX in MTX-bearing PLUVs was 5.47%, and MTX was released slowly from MTX-bearing PLUVs when incubated in phsophate buffered saline, rat plasma and rat liver homogenates.     

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.