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.     

Pharmacodynamics of ZM 241385, a Potent A2a Adenosine Receptor Antagonist,after Enteric Administration in Rat,Cat and Dog

4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) is currently the most selective for the A_2a adenosine receptor antagonist. This paper describes the in-vivo activity of ZM 241385 after administration by both oral and intraduodenal routes. In conscious spontaneously hypertensive rats, ZM 241385 (1–10 mg kg^?1) selectively attenuated the mean arterial blood pressure response produced by exogenous adenosine (1 mg kg^?1 min^?1, i.v.) by up to 45% after oral administration. Activity of ZM 241385 was maintained for at least 6 h after 3 and 10 mg kg^?1 (p.o.). In conscious normotensive cats, ZM 241385 attenuated the blood pressure responses to adenosine (0.6–10 mg kg^?1, i.v.) by 94% after 10 mg kg^?1 (p.o.) and by up to 74% after 0.3 mg kg^?1 (i.v.). Duration of action of ZM 241385 up to 12 h (36% inhibition) was observed after 3 mg kg^?1 (p.o.). In anaesthetized dogs and cats, ZM 241385, after intraduodenal administration (1–10 mg kg^?1), produced a rapid (dose ratio 100-fold 15 min after administration of 10 mg kg^?1 in the cat) and prolonged (dose ratio of 14 at 6 h after administration of 10 mg kg^?1) attenuation of the vasodilatation responses to adenosine receptor stimulation. When administered by this route ZM 241385 was six times more potent than theophylline in the cat and at least twice as potent as theophylline in the dog. In conclusion, ZM 241385 is a potent, selective A_2a adenosine receptor antagonist which is orally active, with a good duration of action by the enteric route in cat, rat and dog. It could therefore be used to evaluate the role of adenosine A_2a receptors in the action of adenosine in-vivo.     

Disposition and bioavailability of the β1-adrenoceptor antagonist talinolol in man

In an open randomized crossover study, the pharmacokinetics and bioavailability of the selective β₁-adrenoceptor antagonist talinolol (Cordanum®—Arzneimittelwerk Dresden GmbH, Germany) were investigated in twelve healthy volunteers (five female, seven male; three poor and nine extensive metabolizers of the debrisoquine hydroxylation phenotype) after intravenous infusion (30 mg) and oral administration (50 mg), respectively. Concentrations of talinolol and its metabolites were measured in serum and urine by HPLC or GC-MS. At the end of infusion a peak serum concentration (C_max) of 631 ± 95 ng mL^?1 (mean ± SD) was observed. The area under the serum concentration-time curve from zero to infinity (AUC_0-∞) was 1433 ± 153 ng h mL^?1. The following parameters were estimated: terminal elimination half life (t_1/2), 10.6 ± 3.3 h; mean residence time, 11.6 ± 3.1 h; volume of distribution, 3.3 ± 0.5 L kg^?1; and total body clearance, 4.9 ± 0.6 mL min^?1 kg^?1. Within 36 h 52.8 ± 10.6% of the administered dose was recovered as unchanged talinolol and 0.33 ± 0.18% as hydroxylated talinolol metabolites in urine. After oral administration a C_max of 168 ± 67 ng mL^?1 was reached after 3.2 ± 0.8h. The AUC_0-∞ was 1321 ± 382 ng h mL^?1. The t_1/2 was 11.9 ± 2.4 h. 28.1 ± 6.8% of the dose or 55.0 ± 11.0% of the bioavailable talinolol was eliminated as unchanged talinolol and 0.26 ± 0.17% of the dose as hydroxylated metabolites by kidney. The absolute bioavailability of talinolol was 55 ± 15% (95% confidence interval, 36–69%). Talinolol does not undergo a relevant first-pass metabolism, and its reduced bioavailability results from incomplete absorption. Talinolol disposition is not found to be altered in poor metabolizers of debrisoquine type.     

Pharmacokinetics of a novel retinoid AGN 190168 and its metabolite AGN 190299 after intravenous administration of AGN 190168 to rats

The pharmacokinetics of AGN 190168, a novel synthetic retinoid, and its major metabolite, AGN 190299, in rat blood after intravenous administration was investigated. Approximately 4.4 mg kg^?1 (high dose) or 0.49 mg kg^?1 (low dose) of AGN 190168 was administered to rats via the femoral vein. Blood was collected from the femoral artery at various time points during an 8 h period. Blood concentrations of AGN 190168 and AGN 190299 were determined by a specific and sensitive high-pressure liquid chromatographic (HPLC) method. AGN 190168 was rapidly metabolized in rats. The only detectable drug-related species in the blood was AGN 190299. Therefore, only pharmacokinetics of AGN 190299 were calculated. Elimination of AGN 190299 appeared to be non-linear after administration of the high dose, and linear after administration of the low dose. The maximum elimination rate (V_max) and the concentration at half of the V_max (k_m), as estimated by a Michaelis—Menten one-compartment model, were 7.58 ± 2.42 μg min^?1 (mean ± SD) and 6.10 ± 1.58 μg mL^?1, respectively. The value of the area under the blood concentration time curve (AUC) was 9.54 ± 1.68 μg h mL^?1 after administration of the high dose and 0.594 ± 0.095 μg h mL^?1 after administration of the low dose. The clearance value was 7.79 ± 1.20 mL min^?1 kg^?1 after the high dose, statistically significantly different from that after the low dose (p < 0.05), 14.0 ± 2.2 mL min^?1 kg^?1. The terminal half-life (t_1/2) was 1.25 ± 0.74 h for the high-dose group and 0.95 ± 0.16 h for the low-dose group. Study results demonstrate rapid systemic metabolism of AGN 190168 to AGN 190299, non-linear pharmacokinetics of AGN 190299 after the 4.4 mg kg^?1 dose, and the lack of difference in disposition profiles between sexes after intravenous administration of AGN 190168 to rats.     

Pharmacokinetics of the novel anticonvulsant hepp after single intravenous administration of three different doses in dogs

HEPP (D, L-3-hydroxy-3-ethyl-3-phenylpropanamide) is a novel compound with a wide spectrum of anticonvulsant activity and relatively low toxicity. The aim of this investigation was to study the pharmacokinetics of HEPP in mongrel dogs and to assess its linearity after intravenous administration of 8, 15, and 30 mg kg^?1. A biphasic disappearance pattern with a rapid distribution phase was observed in the plasma concentration versus time curve. The mean terminal half-life (t_1/2β) was the same after the three doses (3.4±0.15h) and the mean half-lives of the distribution phase (t_1/2α) were not significantly different after the three doses (0.09±0.02, 0.08±0.07, and 0.11±0.03 h for 8, 15, and 30 mg kg^?1 respectively). The mean AUC_0-∞ values were 44.1±10.8, 72.1±8.8, and 127.4±23.2 μg h mL^?1, respectively, showing a linear increase. The individual values of AUC_0-∞ corrected for the administered dose (AUC_0-∞/D) were 0.29±0.04, 0.23±0.05, and 0.22±0.06 h mL^?1. These values were not statistically different. Neither the mean residence time (MRT=4.55±1.50, 4.90±1.32, and 5.07±1.95 h), the steady state volume of distribution (V_ss=0.86±0.11, 1.01±0.17, and 1.20±0.40 L kg^?1) nor the systemic clearance (Cl=3.36±0.82, 3.53±0.44, and 4.02±0.68 mL min^?1 kg^?1) showed significant differences between doses. The values of V_ss suggest that HEPP is distributed in the whole body fluid. The invariant pharmacokinetic parameters and the direct correlation between AUC_0-∞ and the dose suggest that the kinetics of HEPP in dogs are linear over the range of doses studied.     

The pharmacokinetics and absolute bioavailability of selegiline in the dog

Selegiline is beneficial to Parkinsonian patients as an adjunct to levodopa therapy. Currently no pharmacokinetic data are available for selegiline in the literature, mainly due to lack of analytical methods that can measure concentrations below 10 ng mL^?1 in plasma. A sensitive fluorimetric assay based on inhibition of rat brain monoamine oxidase-B (MAO-B) in vitro has been developed to measure selegiline in plasma as low as 0.25 ng mL^?1. The pharmacokinetics of selegiline were investigated following intravenous and oral administration to four female mongrel dogs. Each dog received 1 mg kg^?1 selegiline in solution via gavage or by an intravenous route separated by one week. The mean terminal half-life, volume of distribution of the central compartment, and systemic clearance of selegiline were 60.24 ± 9.56 min, 6.56 ± 0.56 L kg^?1, and 159.91 ± 19.28 mL min^?1 kg^?1, respectively. After oral administration selegiline appeared to be absorbed rapidly with a t_max and C_max of 25 ± 5.8 min and 5.2 ± 1.36 ng mL^?1, respectively. The absolute bioavailability of selegiline in the dog was 8.51 ± 3.31%.     

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.     

Effect of the Selective A1 Adenosine Antagonist 8-Cyclopentyl-1,3-dipropylxanthine on Acute Renal Dysfunction Induced by Escherichia coli Endotoxin in Rats

Abstract— The effect of the selective A₁ adenosine antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPX), on Escherichia coli endotoxin-induced acute renal dysfunction was determined in anaesthetized rats. Bolus administration of endotoxin at doses of either 1 or 20 mg kg^?1 evoked decreases in inulin clearance, renal blood flow, urine flow and excretion of sodium, potassium and chloride. The changes in renal function produced by 20 mg kg^?1 endotoxin were more severe than those noted with 1 mg kg^?1 toxin and, by contrast to this lower dose, renal function showed no signs of recovery. Intravenous administration of CPX (0·1 mg kg^?1) elicited a statistically significant, although modest, attenuation of the decline in inulin clearance, renal blood flow, urine output and electrolyte excretion induced by 20 mg kg^?1 endotoxin. By contrast, treatment with 0·1 mg kg^?1 CPX resulted in statistically significant protection against the falls in excretory function evoked by 1 mg kg^?1 endotoxin but not against the reductions in renal blood flow and inulin clearance produced by the lower dose of toxin. These results suggest that adenosine may play a role, albeit not a major one, in the pathophysiology of endotoxaemic acute renal failure.     

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.     

Dopamine Antagonists Can Inhibit Methamphetamine Sensitization,But Not Cocaine Sensitization,When Assessed by Ambulatory Activity in Mice

Abstract— The repeated subcutaneous administration of methamphetamine (2 mg kg^?1) and cocaine (10 mg kg^?1) at 3–4 day intervals induced sensitization to their ambulation-increasing effects in mice. Subcutaneous administration of SCH 23390 (R-(+)-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0·003–0·03 mg kg^?1) and YM-09151–2 (cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide; 0·003–0·03 mg kg^?1), the selective dopamine D₁ and D₂ antagonists, respectively, reduced dose-dependently the acute ambulation-increasing effect of methamphetamine. The development of methamphetamine sensitization was inhibited when it was administered in combination with either SCH 23390 or YM-09151–2 in the repeated administration schedule. Although SCH 23390 (0·01–0·1 mg kg^?1) and YM-09151–2 (0·01–0·1 mg kg^?1) also reduced the ambulation-increasing effect of cocaine (10 mg kg^?1), neither drug inhibited the cocaine sensitization. Mice given cocaine with SCH 23390 (0·03 mg kg^?1) or YM-09151–2 (0·03 and 0·1 mg kg^?1) showed higher sensitivity than those given cocaine alone. The present results suggest that, although both the dopamine D₁ and D₂ antagonists reduce the acute stimulant effects of both methamphetamine and cocaine, they are only effective for inhibition of the methamphetamine sensitization. Mechanisms other than the dopaminergic system appear to be involved in the cocaine sensitization.     

Pharmacokinetic study of a tripeptide HIV-1 protease inhibitor,KNI-174, in rats after intravenous and intraduodenal administrations

Recently, as a new type of anti-AIDS drug, an HIV-1 protease inhibitor, KNI-174, has been synthesized; it shows a potent and selective HIV-1 protease inhibitory activity in vitro. In this study, we developed an HPLC assay system for KNI-174 in rat plasma and examined the pharmacokinetics of KNI-174 in rats using this assay method after both intravenous (i.v.) and intraduodenal (i.d.) administrations to obtain the disposition characteristics and bioavailability of this new anti-AIDS drug. This HPLC assay method is specific to KNI-174 and the standard curve was linear from 0.02 to 30 μg ml^?1 plasma. After i.v. administration, 10.0 mg kg^?1, KNI-174 disappeared from the rats' plasma in a three-exponential decay. The mean terminal elimination half-life, t_1/2ÀZ, was 3.97 ± 0.19 (S.E.)h, the total body clearance, CL_tot, was 9.53 ± 1.08 ml min^?1 and the distribution volume at steady state, V_{d, ss}′ was 7070 ± 960 ml kg^?1. In the case of the i.d. administration, 10.0 mg kg^?1, the mean peak plasma concentration, C_max, and the peak time, t_max, were 0.196 ± 0.076 μg ml^?1 and 0.444 ± 0.193 h, respectively. The bioavailability of KNI-174 till infinity, BA^(0-infinity), was 5.37 per cent. Because the IC₅₀ of KNI-174 against HIV-1 in PHA-PBM was 138 ng ml^?1, the time needed for maintaining the concentrations above IC₅₀ after a single i.d. administration of KNI-174 is estimated to be 0.350 ± 0.184 h.     

Comparison of a new orally potent tripeptide HIV-1 protease inhibitor (anti-aids drug) based on pharmacokinetic characteristics in rats after intravenous and intraduodenal administrations

Recently, a series of KNI compounds such as KNI-227 and KNI-272 has been synthesized and shows potent and selective HIV-1 protease inhibitory activity in vitro. In this study, we developed an HPLC assay system for KNI-227 and KNI-272 in rat plasma and examined the pharmacokinetic characteristics in rats after both intravenous (i.v.) and intraduodenal (i.d.) administrations to obtain the disposition characteristics and bioavailabilities of these new anti-AIDS drugs. After i.v. administration of KNI-227, 10.0mg kg^?1, the mean terminal elimination half-life, t_1/2λz, was 0.808±0.161(SE)h, the total body clearance, CL_tot, was 11.7±3.3 ml min^?1 and the distribution volume at steady state (V_d,ss) was 1410.460 ml kg^?1. On the other hand, after i.v. administration of KNI-272, 10.0mg kg^?1, t_1/2λz was 2.86±0.78 h, CL_tot was 15.3±1.4 ml min^?1 and V_d,ss was 3440.670 ml kg^?1. In the case of the i.d. administration of drugs, the mean peak plasma concentrations, C_max, of KNI-227 and KNI-272 were 0.374±0.110μg ml^?1 and 0.900±0.093 μg ml^?1, respectively. The bioavailabilities (BA) of KNI-227 and KNI-272 to infinity, BA^(0-∞), were 5.90% and 42.3%, respectively. As compared with the lead compound, KNI-174, the BA of KNI-272 was improved about 10 times. Although the anti-AIDS virus activity of these two drugs has not been investigated in vivo, KNI-272 is expected to be a better candidate for oral anti-AIDS therapies.     

Metabolism,pharmacokinetics and excretion of the GABAA receptor partial agonist [14C]CP-409,092 in rats

1. The metabolism and excretion of a GABA_A partial agonist developed for the treatment of anxiety, CP-409,092; 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (4-methylaminomethyl-phenyl)-amide, were studied in rats following intravenous and oral administration of a single doses of [¹⁴C]CP-409,092.

2. The pharmacokinetics of CP-409,092 following single intravenous and oral doses of 4 and 15?mg kg^?1, respectively, were characterized by high clearance of 169?±?18?ml min^?1 kg^?1, a volume of distribution of 8.99?±?1.46 l kg^?1, and an oral bioavailability of 2.9% ± 3%.

3. Following oral administration of 100?mg kg^?1 [¹⁴C]CP-409,092, the total recovery was 89.1% ± 3.2% for male rats and 89.3% ± 0.58% for female rats. Approximately 87% of the radioactivity recovered in urine and faeces were excreted in the first 48?h. A substantial portion of the radioactivity was measured in the faeces as unchanged drug, suggesting poor absorption and/or biliary excretion. There were no significant gender-related quantitative/qualitative differences in the excretion of metabolites in urine or faeces.

4. The major metabolic pathways of CP-409,092 were hydroxylation(s) at the oxo-tetrahydro-indole moiety and oxidative deamination to form an aldehyde intermediate and subsequent oxidation to form the benzoic acid. The minor metabolic pathways included N-demethylation and subsequent N-acetylation and oxidation.

5. The present work demonstrates that oxidative deamination at the benzylic amine of CP-409,092 and subsequent oxidation to form the acid metabolite seem to play an important role in the metabolism of the drug, and they contribute to its oral clearance and low exposure.

     

Antinociceptive Effect of the Hydroalcoholic Extract of Bauhinia splendens Stems in Mice

The analgesic effect of the hydroalcoholic extract of the stems of Bauhinia splendens (Leguminosae) has been investigated in chemical and thermal models of nociception in mice. The hydroalcoholic extract of B. splendens, 3–60 mg kg^? intraperitoneally or 50–400 mg kg^? orally, caused dose-related, and long-lasting (up to 3 h) inhibition of acetic acid-induced abdominal constriction in mice, with ID50 values of 3.2 and 177.6 mg kg^? and maximum inhibition of 95 ± 2 and 61 ± 6%, respectively. In the formalin test, the extract given intraperitoneally (1.60 mg kg^?) or orally (50–400 mg kg^?) caused graded inhibition of both phases of formalin-induced pain, being about 5- to 6-fold more potent in attenuating the second phase of pain. The calculated mean ID50 values for the first and the second phases were 11.5 and 2.5 mg kg^?, respectively, for intraperitoneal administration and > 200 and 70 mg kg^?, respectively, for oral administration; the percentages of maximum inhibition for the first and the second phases were 68 ± 6 and 99 ± 1, respectively, for intraperitoneal administration and 37 ± 6 and 69 ± 9, respectively, for oral administration. However, at the same doses the extract did not significantly affect the oedematogenic response induced by formalin. The treatment of animals with naloxone (5 mg kg^?, i.p.) completely reversed the analgesic effect caused by morphine (5 mg kg^?, s.c), but had no effect against the antinociceptive effect of the hydroalcoholic extract of B. splendens (60 mg kg^?, i.p.) when assessed against acetic acid-induced abdominal constrictions. Furthermore, the extract, in contrast with morphine, had no analgesic effect in the hot-plate test. These data show that the hydroalcoholic extract of B. splendens has significant analgesic action when assessed against several models of pain. The mechanism underlying its analgesic effect still remains unknown, but seems to be unrelated to interaction with opioid systems.     

Stability and pharmacokinetic studies of a new immunosuppressant,mycophenolate mofetil (RS-61443), in rats

Mycophenolate mofetil (MPM), a new immunosuppressant, is a morpholinoethyl ester of mycophenolic acid (MPA). The enzymatic and non-enzymatic hydrolysis was studied in an artifical digestive fluid, rat plasma, and tissue homogenates. MPM was chemically stable in the artificial digestive fluid. In rat tissue homogenates and plasma, MPM was rapidly hydrolysed to MPA. The conversion rate of MPM to MPA in various rat tissue homogenates was in the order of liver > kidney > plasma > small-intestinal epithelial cells. After the intravenous injection of MPM at 16.7 mg kg^?1, the terminal elimination half-life,-t_1/2β, was 4.74 ± 0.33 (mean ± SD)h, and the area under the plasma concentration versus time curve, AUC, was 48.78 ± 6.01 μg h mL^?1. After intraduodenal (ID) administration of MPM at 16.7 mg kg^?1, t_1/2β was 3.92 ± 1.05 h, and the AUC was 38.08 ± 8.30 μg h mL^?1. The systemic availability of MPA after ID MPM dosing was 1.52 times higher than that after ID administration of MPA. This result supports the usefulness of MPM as an oral produrg of MPA as a new oral immunosuppressant.     

Pharmacokinetic and Pharmacodynamic Aspects of Artelinic Acid in Rodents

Abstract— The efficacy of artelinic acid and artemisinin, orally administered at 10 and 50 mg kg^?1 day^?1, was compared in Plasmodium berghei infected mice. Subsequently, the pharmacokinetics of artelinic acid after intravenous, intramuscular, oral and rectal administration of a 20 mg kg^?1 aqueous solution to rabbits were studied in a four-way randomized cross-over experiment. After intravenous administration, artelinic acid concentrations in blood plasma were high (C₀: 76 ± 15 mg L^?1), and the drug was rapidly eliminated from the central compartment, showing linear elimination kinetics with an elimination half-life of 15 ± 3 min. A large inter-subject variation appeared in the absorption rate and the extent of absorption (2–92%) over the 120 min interval after intramuscular administration. Also, a large inter-subject variation in individual rectal bioavailability (17–100%) was shown, which was dependent on the site of absorption in the rectum. The estimated oral bioavailability was low (4·6 ± 1·7%), probably due to a high first-pass effect and possible decomposition in the acidic gastric environment.     

Lack of interaction between metoclopramide and morphine in vitro and in mice

1.?This study examined interactions via common metabolism or via common pharmacodynamic pathways between frequently co-prescribed metoclopramide (a prokinetic) and morphine (an opioid analgesic).

2.?In human liver microsomes, morphine 3-glucuronide and morphine 6-glucuronide formation had V_max estimates of 6.2 ± 0.07 and 0.75 ± 0.01 (nmole min^?1 mg^?1 protein) and K_m estimates of 1080 ± 37 and 665 ± 55 (µM), respectively. The in vitro K_i for morphine 3-glucuronide formation in the presence of metoclopramide in human liver microsomes or recombinant uridine diphosphoglucuronosyltransferase 2B7 predicted a lack of in vivo interaction.

3.?Morphine (2 mg kg^?1 subcutaneously) delayed gastrointestinal meal transit in mice, metoclopramide (10 mg kg^?1 subcutaneously) had no effect on meal transit, and metoclopramide did not alter this effect of morphine.

4.?Morphine (2 or 5 mg kg^?1 subcutaneously) was antinociceptive in mice (hot plate test) and metoclopramide (10 mg kg^?1 subcutaneously) did not alter the antinociceptive effects of morphine.

5.?Together, the data suggest a lack of interaction between morphine and metoclopramide.     

Pharmacokinetics of the 5-hydroxytryptamine1A agonist 8-hydroxy-2-(N,N-di-n-propylamino)tetralin (8-OHDPAT) in the rat after intravenous and oral administration

1. Plasma levels of ³H and unchanged drug were measured in the non-anaesthetized male rat after intravenous (i.v.) or oral administration of (±)-(R,S)-[propyl-³H]-8-OHD-PAT, at three dose levels per route of administration. The excretion of conjugated metabolites in bile was also studied following i.v. administration.

2. For unchanged 8-OHDPAT following i.v. administration, terminal t_1/2 was 1.56 ± 0.01?h (mean ± SD, n±4), k_elim 0.45 ± 0.01 h^?1, volume of distribution 0.14 ± 0.02 litres and clearance 1.10 ± 0.17 ml min^?1. After oral administration, terminal t_1/2, k_elim apparent volume of distribution and clearance were essentially the same when bioavailability was taken into account. Neither dose size nor route of administration had any significant effect on either terminal t_1/2 or k_elim. Comparison of AUCs following i.v. and oral administration yielded a mean for absolute oral bioavailabiltty of 2.60 ± 0.24%.

3. Comparison of AUCs for total plasma ³H showed that the extent of absorption was 80.1%, indicating that the low oral bioavailability of 8-OHDPAT is due to first-pass metabolism, rather than poor absorption from the GI tract.

4. Following i.v. administration, irrespective of dose, some 10% of the ³H dose was excreted in the bile in 6h, 8.5% as 8-OHDPAT-glucuronide and 1.5% as the glucuronide of the N-despropylated metabolite, 8-OHDPAT. The majority of the biliary excretion occurred within 3?h of dosing.     

Chronic Administration Does Not Alter the Pharmacokinetic Profile of l-Dopa in the Rat

Abstract— Chronic administration of l-dopa (200 mg kg^?1 day^?1 for 12 months) plus carbidopa (25 mg kg^?1 day^?1) or carbidopa (25 mg kg^?1 day^?1) alone did not alter the t½, AUC_0–∞ k₁₀, k₁₂, k₂₁, CL_p or Vd_ss of l-dopa following intra-aortic (i.a.) administration (50 mg kg^?1) alone or after carbidopa (25 mg kg^?1, i.p.) pretreatment, or the t½, AUC_0–∞, t_max or the bioavailability (F) of l-dopa (50 mg kg^?1) administered orally, alone or after acute pretreatment with carbidopa (25 mg kg^?1 i.p.). The peripheral metabolism of l-dopa was unaltered by chronic administration of l-dopa plus carbidopa or carbidopa alone as measured by unaltered AUC_{0·360 min} for 3-O-methyldopa, dopamine, DOPAC or homovanillic acid in the plasma of rats following acute administration of l-dopa (50 mg kg^?1, p.o. or i.a.) alone or following pretreatment with carbidopa, and unaltered hepatic dopa decarboxylase activity.     

Pharmacokinetics and metabolism of NO-1886, a lipoprotein lipase-promoting agent,in cynomolgus monkey

1. The study was conducted to investigate the pharmacokinetics and metabolism of NO-1886 (diethyl 4-[(4-bromo-2-cyanophenyl) carbamoyl] benzylphosphonate) in cynomolgus monkeys.

2. After single intravenous administration of NO-1886 at a dose of 3?mg?kg^?1, the total clearance (CL_tot), area under the plasma concentration–time curve (AUC_0–t), half-life (t_1/2), and volume of distribution (V_d) in cynomolgus monkeys were 531?ml?h^?1?kg^?1, 5.63?µg?h?ml^?1, 0.96?h and 679?ml?kg^?1, respectively. The AUC_0–t for oral administration of NO-1886 (3?mg?kg^?1) was 4.23?µg?h?ml^?1 and the bioavailability was 75%.

3. M-2 (ethyl 4-[(4-bromo-2-cyanophenyl) carbamoyl] benzylphosphonate) and M-3 (4-[(diethoxy-phosphoryl) methyl)] benzoic acid) were present as metabolites in plasma and urine. In faeces, M-2 was present but M-3 was not.

4. The major metabolite of NO-1886 in liver S9 or microsomes was M-2 in the presence of NADPH. On the other hand, M-3 was formed in the absence of NADPH in liver S9 or microsomes and its formation was inhibited by bis-(?p-nitrophenyl) phosphate (BNPP) in liver S9, suggesting that the formation of M-3 was catalysed by carboxylesterase.

5. The findings suggest that the main metabolic pathway of NO-1886 in cynomolgus monkeys is the O-deethylation of NO-1886 to M-2, as in rats and humans, and that the hydrolysis of the amide bond is a minor metabolic pathway.