COMPARATIVE ABSORPTION OF BISMUTH IN SPRAGUE–DAWLEY RATS FOLLOWING ORAL ADMINISTRATION OF PREPARATIONS CONTAINING BISMUTH SUCROSE OCTASULFATE,BISMUTH SUBSALICYLATE,AND BISMUTH SUBCITRATE

The absorption of bismuth from De-Nol (bismuth subcitrate, DN), Pepto-Bismol (bismuth subsalicylate, PB) and bismuth sucrose octasulfate (BISOS) was examined in male Sprague–Dawley rats after a single oral dose of each compound (60 mg bismuth). Bismuth was analysed in blood, urine, kidney, brain, liver, and lung using graphite furnace atomic absorption spectrophotometry. Bismuth C_max averaged 18·4±11·6 ng mL⁻¹ for BISOS, 292±130 ng mL⁻¹ for DN, and 21·5±9·63 ng mL⁻¹ for PB. C_max was significantly lower for BISOS compared to DN (p <0·05) but not significantly different for BISOS compared to PB (p >0·05). Bismuth AUC was 1356±474 ng h⁻¹ mL⁻¹ for BISOS, 2129−452 ng h⁻¹ mL⁻¹ for DN, and 1824−919 ng h⁻¹ mL⁻¹ for PB, which indicated a lower extent of absorption from BISOS compared to DN. Kidney, liver, and lung levels of bismuth were also significantly lower for BISOS compared to DN (p <0·05). Bismuth urinary excretion was significantly lower for BISOS (0·04±0·02%) compared to DN (0·27±0·15%) but not significantly different compared to PB (0·07±·03%). These data suggest that the absorption of bismuth following oral administration of bismuth sucrose octasulfate is significantly lower than that from De-Nol and similar to that from Pepto-Bismol. © 1997 by John Wiley & Sons, Ltd.     

AN INVESTIGATION OF THE DOSE PROPORTIONALITY OF DEFLAZACORT PHARMACOKINETICS

The dose proportionality of deflazacort was assessed following single-dose oral administration at doses of 3, 6, and 36 mg to 24 healthy young adult volunteers. The active metabolite of deflazacort (21-desacetyl deflazacort) was monitored in plasma using a sensitive, semi-microbore liquid chromatographic method. C_max averaged 10·4±5·0, 19·8±7·5, and 132·6±52·5 ng mL⁻¹ for the 3, 6, and 36 mg doses, respectively. AUC(0–∞) averaged 38·5±37·1, 64·9±20·8, and 411·7±148·5 ng h mL⁻¹ for the same three doses, respectively. Elimination half-life ranged from 1·9±0·5 h at the 6 mg dose to 2·4±1·5 h at the 36 mg dose. Regression analyses of dose versus C_max and AUC(0–∞) yielded intercepts which were not significantly different from zero (p>0·05) and slopes which were significant (p<0·05). Regression analysis of dose versus apparent oral clearance yielded a slope which was not significantly different from zero (p>0·05). These data indicate that deflazacort exhibits dose-proportional pharmacokinetics.     

THE INFLUENCE OF TIME OF ADMINISTRATION ON THE PHARMACOKINETICS OF A ONCE-A-DAY DILTIAZEM FORMULATION: MORNING AGAINST BEDTIME

Twenty-three young, healthy, male volunteers received, in a randomized crossover design, 240 mg of a once-a-day diltiazem formulation at 08:00 (AM) or 22:00 (HS) for 6 days. A 7 day washout period was observed between the two modes of administration. Diltiazem plasma concentrations were monitored every hour for 24 h and at 30, 36, and 48 h after the last dose. Differences were found between AM and HS dosing for C_min (mean (SD)=47·2 (25·8) against 39·6 (21·1) ng mL⁻¹, p=0·038), AUC_0–24 (2008 (814) against 1754 (714) ng h mL⁻¹, p=0·024), and AUC_0–48 (2662 (1244) against 2395 (238) ng h mL⁻¹, p=0·034). Overall the two modes of administration did not produce bioequivalent pharmacokinetic profiles. Also HS dosing gave significantly higher plasma concentrations of diltiazem in the early morning hours when the incidence of cardiovascular events is higher. If one assumes a strong correlation between plasma concentrations and myocardial protection then HS dosing should be recommended for QD formulation of diltiazem. Clinical studies should be performed to confirm this theoretical pharmacokinetic advantage.     

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.     

A LIMITED SAMPLING METHOD FOR THE ESTIMATION OF FLUNARIZINE AREA UNDER THE CURVE (AUC) AND MAXIMUM PLASMA CONCENTRATION (CMAX)

A limited sampling model has been developed for flunarizine following a 30 mg oral dose in epileptic patients who were receiving phenytoin or carbamazepine or both, to estimate the area under the curve (AUC) and maximum plasma concentration (C_max). The model was developed using training data sets from 30, 20, 15, or 10 patients at one or two time points. The equations describing the models for AUC using two time points (3 and 24 h) and C_max for the training data set of 30 subjects were AUC_predicted=11·1 C_{3 h}+121·4 C_{24 h}–157 (r =0·80) C_{max(predicted)}=0·036 AUC+42·9 (r =0·74) The model was validated on 64 patients who received flunarizine orally. The model provided reasonably good estimates for both AUC and C_max. The mean predicted AUC of flunarizine was 1230±717 ng h mL⁻¹, whereas the observed AUC was 1203±900 ng h mL⁻¹. The bias of the prediction was 2% and precision was 28%. The mean predicted C_max of flunarizine was 86±32 ng mL⁻¹ as compared to an observed mean C_max of 90±42 ng mL⁻¹. The bias and precision of the prediction were 4% and 24%, respectively. The method described here may be used to estimate AUC and C_max for flunarizine without detailed pharmacokinetic studies. © 1997 by John Wiley & Sons, Ltd.     

THE EFFECT OF FOOD ON THE BIOAVAILABILITY OF IBUPROFEN AND FLURBIPROFEN FROM SUSTAINED RELEASE FORMULATIONS

The effect of food on the plasma concentration–time profile of sustained release dosage forms of ibuprofen and flurbiprofen has been investigated in healthy Asian Indian volunteers, in two separate studies. In study 1, 20 volunteers were administered a single 200 mg multiple-unit sustained release capsule of flurbiprofen (Froben SR^™), after an overnight fast or a heavy vegetarian breakfast. Food produced a statistically significant increase in the mean (±SE) maximal plasma concentration (C_max ) and area under the plasma concentration–time curve (AUC_0–48 . C_max (±SE) increased from 9·88± 0·48 mg L⁻¹ (fasting) to 11·36±0·88 mg L⁻¹ (postprandial) and AUC_0–48 (±SE) increased from 120·78±9·64 mg h L⁻¹ (fasting) to 149·73±12·24 mg h L⁻¹ (postprandial). The mean (±SE) time to peak (t_max ) was also significantly delayed from 3·85±0·27 h to 8·70±0·89 h. In study 2, 18 volunteers were administered a single 800 mg erodible sustained release matrix tablet of ibuprofen (Brufen Retard^™), after an overnight fast or along with a heavy vegetarian breakfast. The formulation exhibited multiple peaks (n≥2) on the plasma concentration–time curve. Although food did not affect the bioavailability of this formulation, there was a statistically significant increase in the mean (±SE) concentration of the first peak (C_peak1 ) from 14·21±1·38 mg L⁻¹ (fasting) to 20·14±1·38 mg L⁻¹ (with food). The time at which C_peak1 was reached was not influenced by the intake of food. Results indicate that while qualitative changes in the plasma concentration versus time curves are primarily influenced by the nature of the formulation and the type of meal, bioavailability is influenced by the absorption characteristics of the drug as well. Thus, despite a significant increase in peak plasma concentrations of both drugs with a meal, the bioavailability of flurbiprofen alone was enhanced.     

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.     

PERCUTANEOUS ABSORPTION AND DISPOSITION STUDIES OF METHOTREXATE IN RABBITS AND RATS

The absorption and disposition of methotrexate (MTX) in the plasma, synovial fluid (SF), skin, and muscle tissue were studied following administration of a topical MTX gel in rabbits and rats. In rabbits, MTX concentrations in the plasma increased steadily toward the peak (5·9 ± 2·8 ng mL⁻¹) which appeared at ∼2 h postdose and declined with the elimination half-life of 4·48 ± 1·74 h. At 1 h after the topical dose, the MTX concentrations in the skin (49·0 ± 19·8 μg g⁻¹), muscle (12·7 ± 3·3 ng g⁻¹), and SF (19·2 ± 10·1 ng g⁻¹) underneath the dosed stifle joint were significantly higher (p <0·05) than those of the untreated stifle joint, indicating the potential therapeutic value of topical delivery of MTX for rheumatoid arthritis. A large fraction (∼59%) of MTX which was found in the skin at 1 h postdose was present in the stratum corneum, indicating its extensive binding capacity for MTX. The MTX concentrations in the muscle and SF of the dosed stifle joint at 1 h postdose were 1·8 and 2·6 times higher than those in the dosed elbow joint, respectively, reflecting the effect of dose site on the permeation of MTX. Using a new filter paper method, the amounts of SF obtained from the elbow and stifle joints of four rabbits were 26·3 ± 8·3 and 48·8 ± 5·2 mg, respectively. A significant enhancer effect of N,N -diethyl-n -toluamide (DEET) on the disposition of MTX in the stratum corneum of rabbit ear was observed (p < 0·05) by the tape-stripping method. In rats, the gel containing 4% DEET resulted in a twofold increase in the permeation of MTX into the muscle over the 4 h period postdose. A modified HPLC method with a linear calibration curve (r > 0·999) over the range of 2–50 ng mL⁻¹, quantitation limit of 0·5 ng mL⁻¹, and mean recovery of ∼87% was used for the quantitation of MTX in the tissue and fluid samples. © 1997 John Wiley & Sons, Ltd.     

PHARMACOKINETIC–PHARMACODYNAMIC MODELLING FOR CAPTOPRIL IN HEALTHY ANAESTHETIZED PIGLETS

The use of the angiotensin converting enzyme inhibitor, captopril, specially in children, has been empirical. This is because the relationship between the pharmacokinetics and pharmacodynamics of captopril has not been clearly defined. It is not usually feasible to obtain the serial kinetic–dynamic data necessary to study this relationship in infants. The piglet was therefore investigated as an animal model in which to study the relationship between the kinetics and dynamics of captopril. The standard pharmacokinetic parameters for captopril in healthy anaesthetized piglets were found to be within the range reported for humans. Cl_TB was estimated to be 1·42±0·33 L h⁻¹ kg⁻¹; t_1/2 was 0·44±0·08 h; V_dss was calculated to be 0·64±0·13 L kg⁻¹; t_1/2 and AUC_0–∞ was estimated to be 145±27 ng h mL⁻¹. The observed haemodynamic response was qualitatively similar to that in humans. Aortic pressure was reduced by 42±18%; heart rate was reduced by 21±11%. A parametric pharmacokinetic (two-compartment)–pharmacodynamic (linear) model has been established to describe plasma captopril concentration and aortic pressure relationship. Based on the observed results, the piglet was considered to be a viable model for our purpose.     

Pharmacokinetics and urinary excretion of DMXBA (GTS-21), a compound enhancing cognition

DMXBA (3-(2, 4-dimethoxybenzylidene)-anabaseine, also known as GTS-21) is currently being tested as a possible pharmacological treatment of cognitive dysfunction in Alzheimer's disease. In this study, plasma and brain pharmacokinetics as well as urinary excretion of this compound have been evaluated in adult rats. DMXBA concentrations were determined by HPLC. Following a 5 mg kg⁻¹ iv dose, DMXBA plasma concentration declined bi-exponentially with mean (±SE) absorption and elimination half-lives of 0.71±0.28 and 3.71±1.12 h, respectively. The apparent steady state volume of distribution was 2150±433 mL kg⁻¹, total body clearance was 1480±273 mL h⁻¹ kg⁻¹, and AUC_0–∞ was 3790±630 ng h mL⁻¹. Orally administered DMXBA was rapidly absorbed. After oral administration of 10 mg kg⁻¹, a peak plasma concentration of 1010±212 ng mL⁻¹ was observed at 10 min after dosing. Elimination half-life was 1.740±0.34 h, and AUC_0–∞ was 1440±358 ng h mL⁻¹. DMXBA peak brain concentration after oral administration was 664±103 ng g⁻¹ tissue, with an essentially constant brain–plasma concentration ratio of 2.61±0.34, which indicates that the drug readily passes across the blood–brain barrier. Serum protein binding was 80.3±1.1%. Apparent oral bioavailability was 19%. Renal clearance (21.8 mL h⁻¹ kg⁻¹) was less than 2% of the total clearance (1480±273 mL h⁻¹ kg⁻¹); urinary excretion of unchanged DMXBA over a 96 h period accounted for only 0.28±0.03% of the total orally administered dose. Our data indicates that DMXBA oral bioavailability is primarily limited by hepatic metabolism. © 1998 John Wiley & Sons, Ltd.     

RELATIVE BIOAVAILABILITY OF FOUR CLOMIPRAMINE HYDROCHLORIDE TABLET PRODUCTS

The relative bioavailability of clomipramine was determined in two single-blind, single-dose, randomized, crossover studies. In the first study, the relative bioavailability of the test product, 2×25 mg clomipramine hydrochloride tablets (Noristan Ltd.), with respect to the reference product, Anafranil^® 2×25 mg tablets (clomipramine HCl; Ciba—Geigy (Pty) Ltd.) was determined. In the second study, the relative bioavailability of the test product, 5×10 mg clomipramine hydrochloride tablets (Noristan Ltd.), with respect to the reference product, Anafranil^® 5×10 mg tablets (clomipramine HCl; Ciba—Geigy (Pty) Ltd.), was determined. The geometric mean values for the variable C_max were 31·.3 ng mL⁻¹ for the reference and 31·.6 ng mL⁻¹ for the test product in study 1. The geometric mean values for the variable AUC were 736 ng h mL⁻¹ and 753 ng h mL⁻¹ for the reference and test, respectively. In study 2, the geometric mean C_max values were 25·.8 ng mL⁻¹ and 23·.9 ng mL⁻¹ for the reference and test respectively; the geometric mean AUC values were 569 ng h mL⁻¹ and 547 ng h mL⁻¹. The 90% confidence intervals for the ‘test/reference’ mean ratios of the plasma clomipramine pharmacokinetic variables C_max and AUC_(0–∞) (as measures of the rate and extent of absorption of clomipramine, respectively) fall within the conventional bioequivalence range of 80–125% for both studies. The test products (clomipramine HCl) are therefore bioequivalent to the reference products (Anafranil^®) with respect to the rate and the extent of absorption of clomipramine in both 10 mg and 25 mg strengths.     

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.     

THE EFFECT OF FOOD ON THE PHARMACOKINETICS OF MULTIPLE-DOSE TERBINAFINE IN YOUNG AND ELDERLY HEALTHY SUBJECTS

Pharmacokinetic (PK) parameters for terbinafine were assessed in 15 elderly and 15 young healthy subjects randomized to receive 250 mg Lamisil^™ once daily for 15 d in a two-period, two-treatment, two-sequence, crossover (fed versus fasted) design within age groups. On each treatment day except days 8 and 15, subjects took Lamisil^™ with food at 8:00 a.m. On days 8 and 15, subjects took the drug under either fed or fasting conditions according to treatment sequence, and 24 h PK profiles were obtained. Two analyses of the pharmacokinetic data were undertaken. In a noncompartmental analysis, AUC_{0–24 h} , C_max , C_{0 h} , and t_max were computed for each subject on each of days 8 and 15, and the influences of food condition and age on these variables were assessed by analysis of variance. AUC_{0–24 h} and C_{0 h} were found to be larger (p <0·5) among elderly subjects than young subjects on day 15, and t_max was prolonged (p <0·05) under the fed condition on day 15. Similar trends on day 8, as well as generally higher exposures under the fed condition on both days, were not statistically significant. A three-compartment model fitted to the complete sequence of 33 terbinafine concentrations measured over 29 d for each subject separately permitted a within-subject assessment of the food effect that confirmed prolonged absorption and increased bioavailability (p <0·05) under the fed condition. Across-subject comparisons of oral clearances estimated with the model also confirmed the increased exposures (lower clearances) among the elderly (p <0·05). The drug was well tolerated in both age groups. In particular, greater drug exposure in the elderly did not result in greater toxicity, as indicated by the safety evaluations in the study. © 1997 by John Wiley & Sons, Ltd.     

Pharkacokinetics and pharmacodynamics of furosemide after direct administration into the stomach or duodenum

The pharmacokinetics and pharmacodynamics of furosemide were compared after an oral administration or a direct administration of Lasix into the duodenum in humans (40 mg). Furosemide was absorbed quickly after a direct administration of Lasix into the duodenum; the peak plasma concentration of furosemide was reached within 1 h in both routes of administration, and the peak concentration was higher in all four subjects after a direct administration into the duodenum than after an oral administration. Furosemide was absorbed considerably after a direct administration of Lasix into the duodenum; the values of the area under the plasma concentration–time curves of furosemide from time zero to 4 h (AUC_{0–4 h}, 93·6 versus 122 μg min mL⁻¹, p <0·123) and the cumulative amounts of the dose excreted in 8 h (10 600 versus 15 000 μg, p <0·0185) and 24 h (11 300 versus 15 400 μg, p <0·0192) urine as unchanged furosemide were significantly higher after a direct administration into the duodenum than after an oral administration. However, the amounts excreted in urine as glucuronide conjugates, a metabolite of furosemide, tended to increase after an oral administration (4030 versus 1670 μg as expressed in terms of furosemide, p <0·0858) when compared to a direct administration into the duodenum, possibly due to the increased gastric first-pass metabolism of furosemide. The 8 h urine output and 8 h urinary excretion of sodium did not increase significantly after a direct administration of Lasix into the duodenum, despite the significantly greater amount of the drug delivered to the active site after a direct administration into the duodenum. This could be explained by the fact that the urinary excretion rates of furosemide after a direct administration into the stomach were closer to the values of maximally efficient urinary excretion rate of furosemide during the 8 h experimental period than after a direct administration into the duodenum. © 1997 John Wiley & Sons, Ltd.     

Design and evaluation of enteric-coated tablets for rifampicin and isoniazid combinations

In order to improve the bioavailability of rifampicin (RIF) from rifampicin and isoniazid (INH) combination formulations, the physicochemical characteristics of RIF, stability of RIF in different pH buffers in the presence of INH, as well as the effect of particle size of RIF materials on the dissolution rate were investigated. On the basis of the above examinations, enteric-coated tablets for RIF and INH combinations were designed and prepared. RIF showed low solubility and high apparent distribution coefficient in the intestinal pH (pH 4.0–7.4). With the decrease in pH, the degradation of RIF increase and the presence of INH deepen the degradation. Enteric-coated tablets were prepared after grinding the RIF materials by dry granulation technique. The pharmacokinetics of RIF and INH of self-made enteric-coated tablets in dogs were studied by comparing with the reference tablets. The AUC_0–48 of RIF in both reference and test tablets were 304.77 ± 42.27 and 353.79 ± 31.63 µg·h·mL^?1, respectively. The AUC_0–48 of INH in both reference and test tablets were 17.14 ± 8.59 and 19.62 ± 10.57 µg·h·mL^?1, respectively. Enteric-coated tablets may minimize the decomposition of RIF in gastrointestinal tract and improve the bioavailability.     

PHARMACOKINETICS OF DA-125, A NEW ANTHRACYCLINE,AFTER INTRAVENOUS ADMINISTRATION TO URANYL NITRATE-INDUCED ACUTE RENAL FAILURE RATS OR PROTEIN--CALORIE MALNUTRITION RATS

The pharmacokinetics of DA-125 were compared after intravenous (i.v.) administration of the drug, 10 mg kg⁻¹, to control male Sprague--Dawley rats ( n=9) and uranyl nitrate-induced acute renal failure (U-ARF, n=12) rats, or male Sprague--Dawley rats fed on a 23% (control, n=8) or a 5% (protein--calorie malnutrition, PCM, n=9) protein diet. After i.v. administration of DA-125, almost ‘constant’ plasma concentrations of M1, M2, and M4 were maintained from 1--2 h to 8--10 h in all rat groups due to the continuous formation of M2 from M1 and M4 from M3. The plasma concentrations of M3 were the lowest among M1--M4 for all rat groups due to the rapid and almost complete conversion of M3 to M4 and other metabolite(s). The AUC_t values of M1 (115 against 82·5 μg min mL⁻¹), M2 (33·0 against 23·6 μg min mL⁻¹), and M4 (26·3 against 15·1 μg min mL⁻¹) were significantly higher in the U-ARF rats than in the control rats. The percentages of i.v. dose excreted in 24 h urine as M1 (under the detection limit against 0·316%), M2 (under the detection limit against 5·58%), and M4 (0·0174 against 0·719%)---expressed in terms of DA-125---were significantly lower in the U-ARF rats than in the control rats, and this could be due to the decreased kidney function in the U-ARF rats. However, the percentages of i.v. dose recovered from the GI tract at 24 h as M1 (0·0532% against under the detcction limit), M3 (0·0286% against under the detection limit), and M4 (0·702% against 0·305%)---expressed in terms of DA-125---were significantly greater in the U-ARF rats than in the control rats. All U-ARF rats had ascites, but the concentrations of M1 (0·0320 μg mL⁻¹), M2 (0·0265 μg mL⁻¹), M3 (under the detection limit), and M4 (0·032 μg mL⁻¹) in the ascites from one rat were almost negligible. The plasma concentrations and most of the pharmacokinetic parameters of M1, M2, and M4 were not significantly different between the PCM rats and their control rats.     

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.     

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.     

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.