PHARMACOKINETICS AND HAEMATOLOGICAL PARAMETERS OF RECOMBINANT HUMAN ERYTHROPOIETIN AFTER SUBCUTANEOUS ADMINISTRATIONS IN HORSES

The pharmacokinetics of recombinant human Epo (rHuEpo) were investigated after subcutaneous administration to horses. Four horses received a single 30 IU kg⁻¹ dose of rHuEpo. One horse received three repeated doses of 120 IU kg⁻¹ at 48 h intervals. Plasma erythropoietin (Epo) was measured by radioimmunoassay. In both cases pharmacokinetic parameters were evaluated using a one-compartment open model and first-order input and output rates. The mean values (±SD) for elimination half-life, CL/F, and V_d/F after a single dose were 12·9±3·34 h, 11·8±4·96 L h⁻¹, and 233±126 L, respectively. After repeated doses, elimination half-life, CL/F, and V_dss/F were 11·3 h, 8·94 L h⁻¹, and 145·6 L, respectively. No significant differences were observed between the haematological parameters after a single 30 IU kg⁻¹ administration compared to baseline values. Multiple and high doses of rHuEpo modified red blood cells, haemoglobin, and hematocrit. According to our results, plasma Epo assay can help, during an antidoping control procedure, to support a positive result only up to 72 h after the last rHuEpo     

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.     

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.     

PHARMACOKINETICS OF ACEBUTOLOL ENANTIOMERS AFTER INTRAVENOUS ADMINISTRATION OF RACEMATE IN A RAT MODEL: A DOSING RANGE COMPARISON

Acebutolol (AC) is a chiral β-adrenergic blocking drug, possessing intrinsic sympathomimetic activity (ISA), and is useful clinically as the racemate in treating hypertension. Utilizing a stereospecific high-performance liquid chromatographic (HPLC) assay, the enantiomeric disposition of AC and its major metabolite diacetolol (DC) are reported after intravenous administration of single 5, 15, 30, and 50 mg kg⁻¹ doses of racemate to male Sprague–Dawley rats. The mean area under the plasma concentration versus time curve (AUC) values display a linear relationship with respect to the administered dose. No statistical differences are observed in apparent volume of distribution (V_d), terminal elimination half-life (t_1/2), total body clearance (Cl_t), or renal clearance (Cl_r) with respect to dose administered. Generally, R–S ratios for AUC following AC administration are statistically different from unity (p < 0·05). However, for the 50 mg kg⁻¹ doses the R–S ratio for AUC is not statistically different from one. For DC, the plasma disposition is nonstereoselective in plasma. The amount of R-DC recovered in urine, however, was greater than that of the antipode (R:S = 1·92 ± 0·29). This study suggests that the enantiomeric disposition of intravenous AC is linear within the investigated range of 5–50 mg kg⁻¹ racemate in rats. © 1997 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.     

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 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.     

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.     

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 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.     

Skin Pigmentation and Pharmacokinetics of Melanotan-I in Humans

A comparative pharmacokinetic trial was performed with a superpotent synthetic melanotropic peptide, [Nle⁴-D-Phe⁷]-α-MSH_1–13 (melanotan-I or MT-I) given by three routes of administration. Plasma levels were measured by RIA and tanning was quantitated using serial reflectometry. Doses of 0·16 mg kg⁻¹ were administered intravenously (IV) and orally (PO), and doses from 0·08 to 0·21 mg kg⁻¹ subcutaneously (SC), in a randomized crossover fashion to three male volunteers over five consecutive days for 2 weeks (ten doses). The results indicate that the SC dose is completely bioavailable compared to the IV dose. No detectable drug levels were observed following PO dosing. The plasma half-lives following SC dosing ranged from 0·07 to 0·79 h for the absorption phase and from 0·8 to 1·7 h for the β-phase. Clearance ranged from 0·12 to 0·19 L kg⁻¹ h⁻¹ and 3·9% or less of the dose was recovered in the urine. Side-effects were minimal, consisting of occasional gastrointestinal upset and facial flushing. Significant tanning of the forehead, arms, and neck was noted following IV or SC dosing. This effect peaked at 1 week following drug administration but was still present 3 weeks after completing the ten-dose regimen. It is concluded that SC administration is an efficacious method of delivering melanotan-I. © 1997 John Wiley & Sons, Ltd.     

Amelioration of Cisplatin Nephrotoxicity with Glycine: Dose Dependency in Rats

The effects of glycine (0·1-1·0 g μg kg^?1, i.v.) on the acute changes in renal haemodynamics and nephrotoxicity produced by cisplatin (6·0 mg g kg^?1, i.v.) were investigated in the rat. Cisplatin produced decreases of 50% in the clearance of [³H] inulin (C_IN) and renal blood flow (RBF), 110 min following its injection. Glycine at a dose of 0·1 g kg^?1 produced no attenuation of the cisplatin-induced decrease in C_IN or RBF. Furthermore, this dose of glycine provided no significant protection of renal function over a 7-day period following cisplatin injection. By contrast, glycine at a dose of either 0·5 or 1·0 g kg^?1 markedly attenuated cisplatin-induced falls in C_IN and RBF, with the highest dose completely preventing any falls in these indices during the course of the experiment. Treatment with these higher doses of glycine produced prominent protection from the nephrotoxic actions of cisplatin, as evidenced by improvements in a range of indices of renal function which included plasma urea and creatinine concentrations, urine output, sodium excretion, C_IN and the clearance of [¹⁴C]P-aminohippurate. The results of experiments with an intermediate dose of 0·25 g kg^?1 glycine revealed some degree of amelioration of acute renal haemodynamic effects of cisplatin, particularly with regard to C_IN; whilst in the nephrotoxicity study, 0·25 g kg^?1 glycine produced a modest but significant reduction in cisplatin-induced acute renal dysfunction. The results have revealed a clear association between the acute renal haemodynamic effects produced by glycine in cisplatin-injected rats with the longer-term renal protective effects of glycine in cisplatin nephrotoxicity. The findings indicate that glycine's ability to prevent the falls in RBF and glomerular filtration rate produced by cisplatin plays an important role in the protective effect of glycine in cisplatin-induced nephrotoxicity.     

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

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

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

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

PHARMACOKINETICS 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.     

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.     

The pharmacokinetics of glycyrrhizin and its restorative effect on hepatic function in patients with chronic hepatitis and in chronically carbon-tetrachloride-intoxicated rats

The relationships between the pharmacokinetic behaviour of glycyrrhizin and its restorative effect for hepatic function were investigated in patients with chronic hepatitis and in rats chronically treated with carbon tetrachloride (CCl₄-treated rats). In patients, the restorative effects in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were 62·2±7·4 and 64·4±7·5%, respectively, after daily 80 mg intravenous (i.v.) doses of glycyrrhizin for 2 weeks, and 63·1±19·1 and 68·7±15·2% after 120 mg doses. The present work suggests that the threshold plasma glycyrrhizin concentration for sufficient effect is near 5 μg mL⁻¹. In rats, the total body clearance (Cl_tot) for glycyrrhizin in the CCl₄-treated rats after i.v. administration of glycyrrhizin (5 mg kg⁻¹ dose) was three-tenths of that of the control, and the t_1/2 for glycyrrhizin was 3·4-fold longer than that of the control. A good correlation was observed between Cl_tot and AST (r=−0·838) or ALT (r=−0·873) activity in both rats. When glycyrrhizin was administered intraperitoneally (i.p.) three times a week for 2 weeks, both the AST and ALT activities in the CCl₄-treated rats showed a greater improvement than for a 10 mg kg⁻¹ dose. Furthermore, the finding on the threshold plasma concentration in patients as above was also supported from the results of the experiments in rats. © 1997 John Wiley & Sons, Ltd.     

Pharmacokinetics and Cardiovascular Effects of YM-21095, a Novel Renin Inhibitor,in Dogs and Monkeys

Abstract— The pharmacokinetics and cardiovascular effects of YM-21095 ((2 RS), (3S)-3-[N^α-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)-butyl]-l-histidylamino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thio]-2-butanol), a potent renin inhibitor, have been studied in beagle dogs and squirrel monkeys. Plasma levels of YM-21095 after 3 mg kg^?1 intravenous dosing to dogs declined biphasically and fitted a two-compartment model. Kinetics were as follows: t½α = 4·9±0·2 min, t½β = 2·76±0·79 h, Vd_ss = 3·86±1·04 L kg^?1, plasma clearance = 2·22 ± 0·39 L kg^?1, and AUC= 1445 ± 266 ng h mL^?1. After 30 mg kg^?1 oral dose, maximum plasma concentration, t_max and AUC of YM-21095 were 28·8 ± 9·6 ng mL^?1, 0·25 h and 23·6 ± 7·7 ng h mL^?1, respectively. Systemic bioavailability as determined on the basis of the ratio of AUC after intravenous and oral dose was 0·16 ± 0·04%. In conscious, sodium-depleted monkeys, YM-21095 at an oral dose of 30 mg kg^?1 lowered systolic blood pressure and inhibited plasma renin activity without affecting heart rate and plasma aldosterone concentration. Maximum plasma concentration of YM-21095 after 30 mg kg^?1 oral dose to monkeys was 71·8 ± 41·5 ng mL^?1, which was reached 0·5 h after the dose. At equihypotensive doses, captopril and nicardipine increased plasma renin activity markedly and slightly, respectively. These results suggest that oral absorption of YM-21095 is low in dogs and monkeys, and YM-21095 shows a blood pressure lowering effect by inhibiting plasma renin activity in sodium-depleted monkeys.     

THE EFFECT OF CHANGES IN GASTRIC pH INDUCED BY OMEPRAZOLE ON THE ABSORPTION AND RESPIRATORY DEPRESSION OF METHADONE

The effect of omeprazole (2 mg kg⁻¹ i.v.) on respiratory depression induced in rats by acute oral methadone administration (5 mg kg⁻¹) was examined and compared with control animals that only received methadone. Quantitative assessments of arterial p_CO2, p_O2, pH, and respiratory rate were employed as criteria for evaluation. Intragastric pH was measured in each rat immediately before and 2 h after methadone. Plasma concentration of methadone was measured for 3 h. The relationship between drug effect and the systemic bioavailability of methadone, measured as the area under the plasma concentration–time curve (AUC_0–180 ), was also evaluated. The intensity of the methadone-induced respiratory depression was significantly greater in the omeprazole group than in control rats. A significant variation (p<0·01) in all respiratory parameters was detected from 30 to 120 min after methadone. Omeprazole caused a significant increase in methadone levels (C_max=156± 6·5 ng mL⁻¹ against 51±5·8 ng mL⁻¹ in control; p<0·05). AUC_0–180 was higher (p<0·05) after omeprazole treatment (18·6±1·4 μg mL⁻¹ min) than in control (6·8± 0·6 μg mL⁻¹ min). Two hours after treatment with omeprazole, intragastric pH values were significantly elevated (4·7±0·1 against 2·2±0·04) and continued increasing, being 6·4±0·1 at the end of the experiment. Correlation was observed between intragastric pH and the area under the effect– (respiratory depression–) time curve (r=0·74; p<0·001). A relationship between plasma methadone levels at 120 min and gastric pH (r=0·92; p<0·001) was detected. A significant correlation between the area under the effect–time curve (0–120 min) and AUC_0–180 has been also observed (r=0·90; p<0·01). These pharmacokinetic and pharmacodynamic changes could be gastric pH dependent because they were mimicked when gastric pH was experimentally modified by bicarbonate whereas opposite results were obtained with acidic pH 2 solution.     

TOXICOKINETIC EVALUATION OF A SELEGILINE TRANSDERMAL SYSTEM IN THE DOG

The toxicology and toxicokinetics of a selegiline transdermal system (STS) were evaluated in a 3 month dog study of daily 24 h applications of placebo 4, 8, or 12 STSs in 32 male and 32 female beagle dogs. Each STS delivered approximately 5 mg selegiline over 24 h. No drug-related signs of toxicity were noted in any group with respect to clinical observations, dermal effects, body weight, food consumption, hematology, urinalysis data, or ophthalmoscopic or electrocardiographic examinations. Clinical chemistry data revealed no consistent adverse effects except for an increase in alanine aminotransferase in dogs receiving 8 and 12 STSs. Histological evaluation of tissues revealed the presence of pigment in the Kupffer cells of dogs treated with 8 and 12 STSs. There were no pathology findings suggestive of hemolysis or cholestasis. The no-effect level (NOEL) was 4 STSs (2·9 mg kg⁻¹ d⁻¹). There were no degenerative or life-threatening toxic effects up to 12 STSs (8·5 mg kg⁻¹ d⁻¹). Gender-related differences in steady-state plasma levels were not observed. Steady-state plasma concentrations were similar to maximum plasma concentrations obtained in single-dose studies, suggesting that drug accumulation was not evident. Simulation of systemic exposure following oral administration of 16·8 mg kg⁻¹ d⁻¹ from previous toxicology studies indicated that selegiline exposure following 12 STSs is sixfold greater while N-desmethylselegiline, L-amphetamine, and L-methamphetamine exposure is 0·5, 0·15, and 0·14 times the exposure in the oral study. The threefold difference in NOEL between oral and transdermal studies in the dog (0·8 versus 2·9 mg kg⁻¹ d⁻¹) is probably related to greater L-amphetamine and L-methamphetamine exposure following oral administration. The reduction in metabolite formation, relative exposure of selegiline in the dog at the NOEL compared to oral toxicology studies, and margin of safety provided, given that the expected clinical dose is less than the dosage of oral Eldepryl^™ (0·15 mg kg⁻¹ d⁻¹), documents the safety of the selegiline drug substance and indicates that additional toxicologic findings with the STS may not be expected. © 1997 by John Wiley & Sons, Ltd.