Effects of morin on the pharmacokinetics of nicardipine after oral and intravenous administration of nicardipine in rats

This study investigated the effects of orally administered morin, an inhibitor of cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp), on the pharmacokinetics of orally and intravenously administered nicardipine in rats. Nicardipine is reportedly a substrate for CYP3A4 and P-gp. Nicardipine was administered orally (12 mgkg(-1)) with or without orally administered morin (1.5, 7.5 and 15 mgkg(-1)), and intravenously (4 mgkg(-1)) with or without orally administered morin (7.5 and 15 mgkg(-1)). In the presence of morin, the pharmacokinetic parameters of nicardipine were significantly altered in the oral group but not in the intravenous group, suggesting that CYP3A-mediated metabolism of nicardipine in the liver is not significantly inhibited by morin. The presence of 7.5 and 15 mgkg(-1) of morin significantly increased (P < 0.01, 67.8-112%) the area under the plasma concentration-time curve and the peak plasma concentration (P < 0.01, 53.5-93.1%) of orally administered nicardipine. The presence of 7.5 and 15 mgkg(-1) of morin significantly decreased (P < 0.01, 40.4-52.8%) the total body clearance of orally administered nicardipine compared with the control group. The enhanced oral bioavailability of nicardipine suggests that intestinal-mediated CYP3A4 metabolism and P-gp-mediated efflux of nicardipine are inhibited by morin. Based on these results, concomitant use of morin or morin-containing dietary supplements with nicardipine may require close monitoring for potential drug interactions.     

Dose-independent pharmacokinetics of torasemide after intravenous and oral administration to rats

After intravenous (at doses of 1, 2, 5, and 10 mg/kg) and oral (at doses of 1, 5, and 10 mg/kg) administration of torasemide, the pharmacokinetic parameters were dose-independent. Hence, the extent of absolute oral bioavailability (F) was also independent of oral doses; the values were 95.6, 98.8, and 97.3% for oral doses of 1, 5, and 10 mg/kg, respectively. The high F values indicated that the first-pass (gastric, intestinal, and hepatic) effects of torasemide in rats could be almost negligible. After intravenous administration, the total body clearances of torasemide were extensively slower than the reported cardiac output in rats and hepatic extraction ratio was only 3-4% suggesting almost negligible first-pass effects of torasemide in the heart, lung, and liver in rats. Based on in vitro rat tissue homogenate studies, the tissues studied also showed negligible metabolic activities for torasemide. Equilibrium of torasemide between plasma and blood cells of rat blood reached fast and plasma-to-blood cells concentration ratio was independent of initial blood concentrations of torasemide, 1, 5, and 10 microg/ml; the mean value was 0.279. Protein binding of torasemide to fresh rat plasma was 93.9 +/- 1.53% using an equilibrium dialysis technique.     

Dose-linear pharmacokinetics of oleanolic acid after intravenous and oral administration in rats

The pharmacokinetics of oleanolic acid was evaluated in vitro and in vivo. From Caco-2 cell permeation studies, oleanolic acid was a low permeability compound with no directional effects, suggesting a low in vivo absorption mediated by a passive diffusion. Oleanolic acid was metabolically unstable following incubation with rat liver microsomes in the presence of NADPH. After intravenous injection at doses of 0.5, 1 and 2 mg/kg doses, oleanolic acid showed dose-linear pharmacokinetics as evidenced by unaltered CL (28.6-33.0 ml/min/kg), Vss (437-583 ml/kg), dose-normalized AUC (16.0-17.9 microg min/ml based on 1 mg/kg) and t1/2 (41.9-52.7 min). Following oral administration of oleanolic acid at doses of 10, 25 and 50 mg/kg, Tmax, t1/2, dose-normalized Cmax (66-74 ng/ml based on 25 mg/kg) and dose-normalized AUC (5.4-5.9 microg min/ml based on 25 mg/kg) were comparable between 25 and 50 mg/kg dose, but the plasma concentrations at 10 mg/kg dose were not measurable as they were below the limit of quantitation (2 ng/ml). The absolute oral bioavailability was 0.7% for oral doses of 25 and 50 mg/kg. The extent of urinary excretion was minimal for both i.v. and oral doses. The very low oral bioavailability of oleanolic acid could be due to a poor absorption and extensive metabolic clearance.     

Methylprednisolone pharmacokinetics after intravenous and oral administration.

1. The pharmacokinetics of methylprednisolone (MP) were studied in five normal subjects following intravenous doses of 20, 40 and 80 mg methylprednisolone sodium succinate (MPSS) and an oral dose of 20 mg methylprednisolone as 4 x 5 mg tablets. Plasma concentrations of MP and MPSS were measured by both high performance thin layer (h.p.t.l.c.) and high pressure liquid chromatography (h.p.l.c.). 2. The mean values (+/- s.d.) of half-life, mean residence time (MRT), systemic clearance (CL) and volume of distribution at steady state (Vss) of MP following intravenous administration were 1.93 +/- 0.35 h, 3.50 +/- 1.01 h, 0.45 +/- 0.12 lh-1 kg-1 and 1.5 +/- 0.63 1 kg-1, respectively. There was no evidence of dose-related changes in these values. The plasma MP concentration-time curves were superimposable when normalized for dose. 3. The bioavailability of methylprednisolone from the 20 mg tablet was 0.82 +/- 0.11 (s.d.). 4. In vivo hydrolysis of MPSS was rapid with a half-life of 4.14 +/- 1.62 (s.d.) min, and was independent of dose. In contrast, in vitro hydrolysis in plasma, whole blood and red blood cells was slow; the process continuing for more than 7 days. Sodium fluoride did not prevent the hydrolysis of MPSS.     

Cocaine pharmacodynamics after intravenous and oral administration in rats: relation to pharmacokinetics

  Rationale: To design optimal dose regimes for oral cocaine, it is essential to characterize pharmacokinetics (PK) of cocaine after IV and PO administration. Objectives: To investigate the absolute bioavailability of oral cocaine, its effectiveness and the relation between PK and PD in a within-subject design. Methods: We used the effects of IV and PO cocaine on a contingency-controlled timing behavior, the differential reinforcement of low rate schedule (DRL 45-s) in 3-h sessions, as the PD measures [i.e., the shorter-response rate (srr) and the reinforcement rate (rr)]. Cocaine PK parameters were determined by simultaneous modeling of the concentration-time profiles (CTPs) after IV 2 mg/kg and PO 20 mg/kg cocaine administration. The absolute oral cocaine bioavailability was determined pharmacokinetically (F) and pharmacodynamically (F_srr and F_rr). Results: IV and PO cocaine increased the shorter response rate and decreased the reinforcement rate in a dose- and time-related fashion, which mirrored the respective prototypical serum cocaine CTPs. After the absorption phase, the serum cocaine CTP of PO cocaine paralleled that of IV cocaine. The duration of action for PO cocaine was longer than that for IV cocaine owing to its larger mean residence time. The active metabolite, norcocaine, was not detected after IV but after PO cocaine administration. The value of F was 4.66% which was significantly lower than the values of F_srr (13.67%) and F_rr (32.63%). Furthermore, the concentration-effect relations for the reinforcement rate revealed that PO cocaine was more potent than IV cocaine. Conclusions: Oral cocaine is more effective behaviorally than from predictions made in terms of its PK. The differences in active metabolite profiles as well as the rate and extent of acute tolerance for IV versus PO cocaine may account for the greater potency observed for oral cocaine. Received: 23 July 1998 / Final version: 2 February 1999     

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

Rationale

Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine.

Objective

The major aims were to investigate the pharmacokinetics and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model.

Methods

Mephedrone was administered to male Sprague–Dawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180–240 min.

Results

Mephedrone plasma concentrations after i.v. administration fit a two-compartment model (α?=?10.23 h^?1, β?=?1.86 h^?1). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10 % and the percentage of mephedrone protein binding was 21.59?±?3.67 %. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85?±?0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokinetic–pharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect.

Conclusions

We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude, and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity.     

Effects of cyclosporin on the pharmacokinetics of propranolol after intravenous and oral administration to control rats and to rats with uranyl nitrate-induced acute renal failure

The effects of cyclosporin on the pharmacokinetics of propranolol have been investigated after intravenous and oral administration of the drugs to control rats and to rats with uranyl nitrate-induced acute renal failure. The effects of intravenous cyclosporin, 30 mg kg(-1), on the pharmacokinetics of intravenous propranolol, 3 mg kg(-1), were significant both in control rats and in rats with uranyl nitrate-induced acute renal failure; after intravenous administration of cyclosporin plasma concentrations of propranolol were significantly lower, the area under the plasma concentration-time curve (AUC) for propranolol from time zero to time infinity was significantly smaller, and the time-averaged total body clearance of propranolol was significantly faster. The effects of oral cyclosporin, 100 mg kg(-1), on the pharmacokinetics of oral propranolol, 10 mg kg(-1), were also significant, both in control rats and in rats with uranyl nitrate-induced acute renal failure; after administration of oral cyclosporin plasma concentrations of propranolol were significantly higher and the AUC of propranolol was significantly greater. These data suggest that cyclosporin increases the elimination of propranolol, and that the first-pass effects of propranolol are reduced, or gastrointestinal absorption of propranolol is increased, or both, by cyclosporin.     

Pharmacokinetics of verproside after intravenous and oral administration in rats

Verproside, a catalpol derivative iridoid glucoside isolated from Pseudolysimachion longifolium, is a candidate for anti-asthmatic drug. The dose-dependency of the pharmacokinetics of verproside was evaluated in rats after intravenous and oral administration. After intravenous administration of verproside (2, 5 and 10 mg/kg doses), the systemic clearance (Cl) was significantly reduced and AUC was significantly increased at 10 mg/kg dose compared to 2 and 5 mg/kg doses. The volume of distribution at steady state (V _ss) remained unchanged as the dose was increased. The extent of urinary excretion was low for both intravenous (3.3–6.2%) and oral (0.01–0.04%) doses. Isovanilloylcatalpol was identified as a metabolite after intravenous administration of verproside and showed the significant decreases in AUC and C _max at 10 mg/kg verproside dose. The reduced systemic clearance of verproside at high doses appears to be due to the saturable metabolism. Upon oral administration of verproside (20, 50 and 100 mg/kg doses), C _max was nonlinearly increased. The extent of verproside recovered from the gastrointestinal tract at 24 h after oral administration was 0.01–0.72% for all three doses studied. The absolute oral bioavailability (F) was 0.3 and 0.5% for 50 and 100 mg/kg doses, respectively. Low F appears to be due to first-pass metabolism.     

Pharmacokinetics of dihydroergosine in rats after intravenous and oral administration

Wistar rats received an intravenous dose of 20 micrograms/kg and an oral does of 40 micrograms/kg 3H-Dihydroergosine. Concentrations of radioactivity were measured in plasma, bile, urine, and faeces, and pharmacokinetical parameters of an open two compartment model were calculated. After intravenous injection and oral administration 3H-Dihydroergosine is rapidly lost from the central compartment with distribution rate constants alpha = 0.889 h-1 and beta = 0.722 h-1, respectively. Biological half life in the elimination phase after both application is nearly the same t 1/2 = 13.6 h. The volume of central compartment is Vc = 3.075 l/kg and the volume of distribution Vd beta = 30.75 l/kg. The fraction of 3H-Dihydroergosine absorbed after oral administration, calculated from areas under the curves upon oral and intravenous administration, is 31%. The percentage of 3H-radioactivity eliminated with bile was 98.3% of the dose within 72 hours after intravenous and 29.3% after oral administration. The main portion of the administered 3H-radioactivity was recovered in faeces -66.1% after intravenous and 81.3% after oral administration, while only 17.4% and 4.9% of the administered dose was eliminated in the urine within 120 hours, respectively.     

Disposition and pharmacokinetics of naltrexone after intravenous and oral administration in rhesus monkeys

The purposes of this investigation were to determine the disposition of naltrexone (NTX) in monkeys and assess the role of first-pass metabolism and enterohepatic cycling in the disposition process. Concentrations of naltrexone and three metabolites were determined in plasma and urine as a function of time after po and iv NTX administration in six monkeys. Urinary recovery of NTX and metabolites 0-48 hr after iv administration (10 mg/kg) totaled 52% of the dose. Recovery in feces was minimal. Total urinary excretion of NTX and metabolites after po administration was 89% of that after iv administration, suggestive of good absorption of NTX from solution. However, the area under the plasma level-time curve for NTX after po administration was only 3.6% of that after iv administration, indicating a very high first-pass effect. The calculated extraction ratio was 0.96-0.99. Analysis of plasma level-time and urinary excretion rate-time data for NTX, conjugated NTX, beta-naltrexol, and conjugated beta-naltrexol after iv administration revealed that 1) the decline of plasma levels or urinary excretion rates with time for the conjugated metabolites was parallel to the decline for the apparent precursor; 2) the decline of plasma levels or urinary excretion rates for beta-naltrexol was slower than for naltrexone; and 3) there is evidence for a pronounced enterohepatic cycling of conjugated NTX and conjugated beta-naltrexol that influences the plasma level-time profile of these conjugates and the unconjugated compounds as well.     

The clinical pharmacokinetics of buflomedil in normal subjects after intravenous and oral administration

Summary A dose-ranging pharmacokinetic study of buflomedil was carried out in eight subjects to determine the pharmacokinetic parameters of the drug after oral and intravenous administration. Based on AUC analyses, the pharmacokinetics of buflomedil were found to be linear within the dose ranges studied (50 to 200 mg for i. v. injection and 150 to 450 mg for oral administration). In the oral study, the mean biological half-life of the drug was 2.97 h, while after intravenous dose it was 3.25 h. The apparent volume of distribution after the pseudodistribution equilibrium (F_d) and volume of distribution at the steady state (V_dss) were 1.43±0.24 l/kg and 1.32±0.26 l/kg, respectively. The mean urinary recovery of intact drug and the metabolite, paradesmethyl buflomedil, after intravenous dosing, were 23.6% and 18.7%, respectively, while after oral dosing, they were 18% and 14.8%, respectively. On the average, 72% of the dose was obserbed into the systemic circulation after oral administration. This level of bioavailability was attributed to the hepatic first-pass effect.     

Comparison of dexamethasone pharmacokinetics in female rats after intravenous and intramuscular administration

This study seeks a route of drug administration that would produce a pharmacokinetic profile for dexamethasone not significantly different from the intravenous route in female rats and would offer reproducible drug input with minimal stress to the animals. The intramuscular (i.m.) route of drug administration vs intravenous (i.v.) injection were compared in three female Wistar rats administered 1 mg/kg dexamethasone phosphate. Dexamethasone plasma concentrations were measured by a normal phase HPLC assay for 12 h after drug administration. Dexamethasone exhibited monoexponential behavior after intravenous dosing and was absorbed rapidly after intramuscular dosing (absorption half-life of 14 min) with 86% bioavailability. Dexamethasone had a terminal half-life of 2.3 h after drug administration by either route. The volume of distribution of 0.78 l/kg and the clearance of 0.23 l/h/kg are in good agreement with reported pharmacokinetic parameters in male rats. Intravenous dosing can be replaced by intramuscular dosing without causing any marked difference in dexamethasone pharmacokinetics.     

Pharmacokinetics of alpha-dihydroergocryptine in rats after intravenous and oral administration.

The pharmacokinetic properties of alpha-dihydroergocryptine methanesulphonate (alpha-DHEK, CAS 19467-62-0) were investigated in rat using a radioimmunoassay technique for nonmetabolized drug. alpha-DHEK, intravenously administered at the dose of 6 mg/kg, showed a plasma profile according to an open 3-compartment pharmacokinetic model with a long half-life (about 7.56 h). The kinetics of alpha-DHEK after oral administration (6 mg/kg) showed two peaks; the second peak at 8 h was probably due to an enterohepatic cycle. The disposition of alpha-DHEK consisted in a fast absorption and a slow elimination (t1/2el about 6.78 h). The alpha-DHEK was largely metabolized as results from the complex metabolite profile in body fluids and from very low urinary elimination of unchanged drug.     

Noopept pharmacokinetics after intravenous administration of a lyophilized medicinal form in rats

The pharmacokinetics of noopept, a dipeptide drug possessing nootropic and neuroprotective properties, were evaluated in rats after the intravenous administration of its novel formulation for injections prepared using lyophilization in the presence of mannitol. The pharmacokinetic characteristics of the new preparation are comparable with those of aqueous solutions of the parent substance and can be recommended for further investigation and implementation into medical practice. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 3, pp. 6–8, March, 2007.     

Changes in metformin pharmacokinetics after intravenous and oral administration to rats with short-term and long-term diabetes induced by streptozotocin

It has been reported that metformin was primarily metabolized via hepatic CYP2C11, 2D1, and 3A1/2 in rats, and the expression and mRNA levels of hepatic CYP2C11 and 3A1 decreased and increased, respectively, whereas the expression of CYP2D1 was not changed in rat model of diabetes induced by streptozotocin (DMIS). Also minimizing the toxic effects of streptozotocin by carrying out experiments 4-5 weeks after streptozotocin injection has been reported. Thus, the pharmacokinetics of metformin was evaluated in rat model of DMIS at the 7th and the 29th days after streptozotocin injection. After intravenous administration of metformin (100 mg/kg) to rat model of DMIS, the CL(R) became significantly faster (46.9% and 77.8% increase for the 7th and the 29th days, respectively; due to urine flow rate-dependent timed-interval renal clearance of the drug) and CL(NR) became significantly slower (28.0% and 34.3% decrease, respectively; due to decreased hepatic CYP2C11) than in their respective controls. After oral administration of metformin (100 mg/kg) to rat model of DMIS, the AUC became significantly smaller (18.6% and 33.7% decrease for the 7th and the 29th days, respectively) than in their respective controls. The CL(NR) of metformin were comparable between two rat models of DMIS.     

Effects of bile salts on the lovastatin pharmacokinetics following oral administration to rats

This study aimed to examine the effects of bile salts on pharmacokinetics of lovastatin, which has low bioavailability. Lovastatin solid dispersions were prepared using sodium deoxycholate (NaDC) and sodium glycholate (NaGC) at ratios of 1:19, 1:49, and 1:69. The formulated solid dispersions and control (commercial tablet) were administered to rats and plasma concentrations were determined by a validated LC-MS/MS method. Statistically significant differences were found in C_max, AUC_0–10, and AUC_0–∞ values among lovastatin formulations (p?<?0.05). NaDC-containing formulations revealed higher bioavailabilities than NaGC-containing solid dispersions at ratios of 1:19 and 1:49. Especially, NaDC-containing formulation at a ratio of 1:19 (NaDC19) showed the highest bioavailability. The AUC (both AUC_0–10 and AUC_0–∞) of NaDC19 was statistically higher than control and NaDC69 (p?<?0.05). The AUC values decreased as bile salt concentrations increased. Overall, formulations containing bile salts showed higher AUC values than control, even though all formulations did not show significantly higher AUC. In conclusion, the addition of bile salts to lovastatin could enhance drug bioavailabilities. However, too high concentrations of bile salts could decrease bioavailabilities of lovastatin.