Enantioselective assay of nimodipine in human plasma using liquid chromatography-tandem mass spectrometry.

Nimodipine is a dihydropyridine calcium channel blocker that exhibits higher selectivity toward cerebral blood vessels compared with other members of the same class. It has been shown to improve outcomes and prevent delayed cerebral ischemia in the setting of aneurysmal subarachnoid hemorrhage, a life-threatening brain bleed. Nimodipine is a chiral compound and it is marketed as a racemic mixture of (+)-R and (-)-S enantiomers. (-)-S-Nimodipine is approximately twice as potent a vasorelaxant as the racemic mixture and is more rapidly eliminated than the (+)-R counterpart following oral dosing. Few analytical procedures have been reported to determine nimodipine enantiomers in biological samples; however, the reported methods were time-consuming, involved multistep extraction procedures and required large sample volumes. Herein, we present an LC-MS/MS method for quantifying nimodipine enantiomers in human plasma using a small sample volume (0.3 ml) and a single liquid-liquid extraction step. The peak area ratios were linear over the tested concentration ranges (1.5-75 ng/ml) with r2 > 0.99. The intraday CV and percentage error were within ±14% while the interday values were within ±13%, making this analytical method feasible for research purposes and pharmacokinetic studies.

SFC-MS/MS method for simultaneous determination of nimodipine and 3-n-butylphthalide in beagle plasma: application to pharmacokinetic interaction study.

Aim: Nimodipine and 3-n-butylphthalide are co-administered to treat vascular dementia, but the pharmacokinetic interaction between the two drugs is still unknown. Therefore, a robust, high-throughput and economical supercritical fluid chromatography-ESI-MS/MS method has been initially developed to simultaneously determine nimodipine and 3-n-butylphthalide in beagle plasma, in order to study the safety of co-administration. Materials & methods: After a simple protein precipitation procedure, isocratic elution with mobile phase of CO2 and methanol (containing 0.3% formic acid and 2 mM ammonium acetate) was applied to minimize run time and facilitate sensitive and high-throughput bioanalysis. The method was fully validated according to US FDA Guidance. The validated method was then successfully applied in a pharmacokinetic interaction study. Results: The results indicated there is no significant pharmacokinetic interaction between the two drugs.

Comparative Pharmacokinetics of Nimodipine in Rat Plasma and Tissues Following Intraocular, Intragastric, and Intravenous Administration.

We investigated the pharmacokinetics of nimodipine (NMD) in rats plasma and tissues following intraocular (io), intragastric (ig), and intravenous (iv) administration at doses of 5.0 mg/kg io and iv and 10.0 mg/kg ig. After a single dose of NMD, plasma, heart, liver, spleen, lung, kidney, and brain samples were collected at the scheduled time points. The concentration of NMD in rat plasma and tissues was determined by high-performance liquid chromatography, and the main pharmacokinetic parameters were calculated and compared. NMD was rapidly absorbed and reached the maximum plasma concentration in approximately 5 min after io administration. The absolute bioavailability after io administration was higher than that after ig administration (40.05% vs. 5.67%). There were significant differences in the tissue distribution of NMD with different administration routes. After io administration, NMD was distributed more in the lung, spleen, and brain tissues, and less in the kidney. The maximum drug concentration after io administration in the heart, liver, spleen, lung, kidney, and brain was 1.00, 0.47, 2.02, 1.47, 0.22, and 5.79 times higher than that after via ig administration, and the area under the curve value was 0.59, 0.78, 1.71, 1.84, 0.25, and 4.59 times greater, respectively. Nimodipine appears to achieve systemic effects via io administration. Compared with ig, io administration could significantly increase NMD distribution in the brain tissue, indicating that NMD could be delivered to the brain via io administration.

Development of a sensitive and rapid UHPLC-MS/MS method for simultaneous quantification of nine compounds in rat plasma and application in a comparative pharmacokinetic study after oral administration of Xuefu Zhuyu Decoction and nimodipine.

Xuefu Zhuyu Decoction (XFZYD) is a traditional Chinese medicine prescription used for the clinical treatment of traumatic brain injury (TBI). The purpose of this work was to develop a sensitive and rapid UHPLC-MS/MS method to simultaneously study the pharmacokinetics of nimodipine and eight components of XFZYD, namely, amygdalin, hydroxysafflor yellow A, rutin, liquiritin, narirutin, naringin, neohesperidin and saikosaponin A, in rats with and without TBI. Multiple reaction monitoring was highly selective in the detection of nine analytes and the internal standard without obvious interference. The calibration curves displayed good linearity (r > 0.99) over a wide concentration range. The mean absolute recoveries of the nine analytes were 85-106%, and all matrix effects were in the range 80-120%. The intra- and inter-day precision and accuracy were acceptable (RSD, <15%; RE%, ±20%). The validated method was successfully applied to compare the pharmacokinetics in four experimental groups, including control rats orally administered XFZYD and TBI model rats orally administered XFZYD, XFZYD and nimodipine, or nimodipine alone. The results showed that herb-drug interactions occurred between XFZYD and nimodipine in the treatment of TBI, nimodipine affected the pharmacokinetics of XFZYD, and XFZYD affected the absorption, distribution and excretion of nimodipine in vivo.

The use of amphiphilic copolymer in the solid dispersion formulation of nimodipine to inhibit drug crystallization in the release media: Combining nano-drug delivery system with solid preparations.

Solid dispersion is a widely used method to improve the dissolution and oral bioavailability of water-insoluble drugs. However, due to the strong hydrophobicity, the drug crystallization in the release media after drug dissolution and the resulted decreased drug absorption retards the use of solid dispersions. It is widely known that the amphiphilic copolymer can encapsulate the hydrophobic compounds and help form stable nano-dispersions in water. Inspired by this, we tried to formulate the solid dispersion of nimodipine by using amphipathic copolymer as one of the carriers. Concerning the solid dispersions, there are many important points involved in these formulations, such as the miscibility between the drug and the carriers, the storage stability of solid dispersions, the dissolution enhancement and so on. In this study, a systemic method is proposed. In details, the supersaturation test and the glass transition temperature (Tg) measurement to predict the crystallization inhibition, the ratios of different components and the storage stability, the interactions among the components were investigated in detail by nuclear magnetic resonance (1H NMR) and isothermal titration calorimetry (ITC) and, the final dissolution and oral bioavailability enhancement. It was found that the amphiphilic copolymer used in the solid dispersion encouraged the formation the drug loading micelles in the release media and, finally, the problem of drug crystallization in the dissolution process was successfully solved.

Development and optimization of a supercritical fluid chromatography tandem mass spectrometry method for the high-throughput determination of nimodipine in beagle plasma.

A simple, sensitive, and efficient supercritical fluid chromatography with tandem mass spectrometry method was established for the determination of nimodipine in beagle plasma. One-step protein precipitation with acetone was used to extract the analytes from the plasma. Nitrendipine was used as the internal standard. The chromatographic separation was achieved on an ACQUITY UPC2 ™ BEH 2-EP column, and a gradient elution program was applied at a flow rate of 1.5 mL/min. The detection was carried out on a triple quadrupole tandem mass spectrometer with an electrospray ionization source operating in positive ion mode. Quantification was performed using multiple reaction monitoring of the transitions of m/z 419.3→301.3 for nimodipine and m/z 361.4→315.2 for nitrendipine. A satisfactory linearity was obtained over the concentration range of 0.5-800 ng/mL (r > 0.996). The intra- and interday precision and accuracy results were <9.1% across the quality control levels. The peak concentration and area under concentration-time curve (0-720 min) values of the test and reference formulations were 279.28 ± 211.46 and 265.13 ± 149.26 ng/mL, 25608.00 ± 17553.65 and 28553.67 ± 20207.92 ng·min/mL, respectively. The validated method was successfully applied to reveal the pharmacokinetic profiles of nimodipine in beagle dogs after oral administration. Moreover, the analytical method could be used for further bioequivalence studies.

Preparation and characterization of nimodipine-loaded nanostructured lipid systems for enhanced solubility and bioavailability.

PURPOSE: Nimodipine (NMP) is a clinical dihydropyridine calcium antagonist. However, the clinical application of NMP is limited by poor water solubility and low oral bioavailability. To overcome these drawbacks, this study designed optimal NMP-incorporated nanostructured lipid carriers (NLCs). METHODS: High-pressure homogenization was successfully applied to prepare NMP-NLC, and the nanoparticle morphology was observed by a transmission electron microscope. The existence form of NMP in NMP-NLC was investigated by powder X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy, respectively. The in vitro release study was performed by the dialysis method, and in vivo studies including in situ intestinal perfusion and pharmacokinetics were investigated in rats with NMP detected by high-performance liquid chromatography. RESULTS: The obtained NMP-NLC shared a spherical shape of ~70 nm with a smooth surface and high encapsulation efficiency of 86.8%±2.1%. Spectroscopy indicated that the drug was in an amorphous state. The NMP-NLC exhibited a sustained release and diverse release profiles under different release medium, which mimicked the physiological environment. Moreover, an in situ intestinal perfusion experiment revealed that NMP-NLC could be mainly absorbed by the small intestine. Remarkable improvements in Cmax and AUC0-∞ from NMP-NLC were obtained from pharmacokinetic experiments, and the relative bioavailability of NMP-loaded nanostructured lipid systems was 160.96% relative to NMP suspensions. CONCLUSION: Collectively, the NLCs significantly enhanced the oral bioavailability of NMP and might provide a promising nanoplatform for hydrophobic drug delivery.

Pegylated nanoparticles for the oral delivery of nimodipine: Pharmacokinetics and effect on the anxiety and cognition in mice.

Nimodipine may be of interest to treat behavioral alterations and memory deficits. However, its oral administration is hampered by a low bioavailability. The aim of this work was to develop pegylated nanoparticles as oral carriers of nimodipine and test their capability to both reverse the anxiety and protect against cognitive impairment of in stressed mice. Pegylated nanoparticles (NMD-NP/PEG), with a size of 190 nm and a payload of 68 µg/mg, significantly improve the oral bioavailability of nimodipine; about 7-times higher than for the control drug solution (62% vs 9%). The effect of oral nimodipine on the anxiety and cognitive capabilities in a model of stressed mice was also evaluated. NMD-NP/PEG displayed a poor effect on the anxiety-like behavior of animals. Nevertheless, only the treatment with NMD-NP/PEG exerted a protective effect against the memory impairments induced by chronic corticosterone administration, improving the cognitive capabilities of animals when compared with controls. These pegylated nanocarriers may represent a useful strategy to develop new oral treatments for preventing from cognitive impairments.

In vitro and in vivo evaluation of hypothermia on pharmacokinetics and pharmacodynamics of nimodipine in rabbits.

Objective To investigate the effect of hypothermia on the pharmacokinetics and pharmacodynamics of nimodipine in rabbits using in vivo and in vitro methods. Methods Five healthy New Zealand rabbits received a single dose of nimodipine (0.5 mg/kg) intravenously under normothermic and hypothermic conditions. Doppler ultrasound was used to monitor cerebral blood flow, vascular resistance, and heart rate. In vitro evaluations of protein binding, hepatocyte uptake and intrinsic clearance of liver microsomes at different temperatures were also conducted. Results Plasma concentrations of nimodipine were significantly higher in hypothermia than in normothermia. Nimodipine improved cerebral blood flow under both conditions, but had a longer effective duration during the hypothermic period. Low temperature decreased the intrinsic clearance of liver microsomes, with no change in protein binding or hepatocyte uptake of nimodipine. Conclusion Nimodipine is eliminated at a slower rate during hypothermia than during normothermia, mainly due to the decreased activity of cytochrome P450 enzymes. This results in elevated system exposure with little enhancement in pharmacological effect.

Systemic and Cerebral Concentration of Nimodipine During Established and Experimental Vasospasm Treatment.

BACKGROUND: Oral nimodipine is an established prophylactic agent for cerebral vasospasm after subarachnoid hemorrhage (SAH). In highly selected cases, intra-arterial (IA) or intravenous (IV) application of nimodipine may be considered; however, the optimum dosage and modality of application remain a matter of debate. The purpose of this investigation is analysis of nimodipine concentration in serum, cerebrospinal fluid, and cerebral microdialysate in the context of currently effective dose and route of application (oral, IA, IV). METHODS: We prospectively collected 156 samples from 37 patients treated for aneurysmal SAH from May 2014 to July 2015. Treatment groups were stratified according to modality of application and low-dose or high-dose treatment. At time of sampling, current dose and modality of application effectively sustained cerebral perfusion as documented by common diagnostics. Samples were analyzed for nimodipine concentration via high-performance liquid chromatography and tandem mass spectrometry. RESULTS: In most cases (94.3%), nimodipine remained below the limit of quantification (0.5 ng/mL) within the brain (microdialysis, cerebrospinal fluid), even during targeted, local application (IA nimodipine). The median serum concentration for all treatment groups was 17.3 ng/mL. Modality of application (oral, IA, IV) was not associated with significant differences in serum concentrations (P = 0.712), even after stratification for dosage (P = 0.371), implying a comparable systemic distribution, if not efficacy. CONCLUSIONS: Nimodipine does not accumulate sufficiently within the target organ for treatment monitoring. Comparable systemic concentrations can be observed irrespective of application modality and dosing. Future studies will clarify the role of efficacy-driven treatment algorithms, in which lowest dose and least invasive mode of application still effective should be identified.

Development of two step liquid-liquid extraction tandem UHPLC-MS/MS method for the simultaneous determination of Ginkgo flavonoids, terpene lactones and nimodipine in rat plasma: Application to the pharmacokinetic study of the combination of Ginkgo biloba dispersible tablets and Nimodipine tablets.

A sensitive, reliable and accurate UHPLC-MS/MS method has been firstly established and validated for the simultaneous quantification of ginkgo flavonoids, terpene lactones and nimodipine in rat plasma after oral administration of Ginkgo biloba dispersible tablets, Nimodipine tablets and the combination of the both, respectively. The plasma samples were extracted by two step liquid-liquid extraction, nimodipine was extracted by hexane-ether (3:1, v/v) at the first step, after that ginkgo flavonoids and terpene lactones were extracted by ethyl acetate. Then the analytes were successfully separated by running gradient elution with the mobile phase consisting of 0.1% formic acid in water and methanol at a flow rate of 0.6mL/min. The detection of the analytes was performed on a UHPLC-MS/MS system with turbo ion spray source in the negative ion and multiple reaction monitoring (MRM) mode. The calibration curves for the determination of all the analytes showed good linearity (R(2)>0.99), and the lower limits of quantification were 0.50-4.00ng/mL. Intra-day and inter-day precisions were in the range of 3.6%-9.2% and 3.2%-13.1% for all the analytes. The mean extraction recoveries of the analytes were within 69.82%-103.5% and the matrix were within 82.8%-110.0%. The validated method had been successfully applied to compare the pharmacokinetic parameters of ginkgo flavonoids, terpene lactones and nimodipine in rat plasma after oral administration of Ginkgo biloba dispersible tablets, Nimodipine tablets with the combination of the both. There were no statistically significant differences on the pharmacokinetic behaviors of all the analytes between the combined and single administration groups. Results showed that the combination of the two agents may avoid dosage adjustments in clinic and the combination is more convenient as well as efficient on different pathogenesis of cerebral ischemia.

Simple and validated UHPLC-MS/MS analysis of nimodipine in plasma and cerebrospinal fluid of patients with subarachnoid haemorrhage.

We present a simple, fast and validated method for the determination of nimodipine in plasma and cerebrospinal fluid (CSF) of patients with subarachnoid haemorrhage using ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Plasma or CSF 250µL aliquots were pretreated with acetonitrile spiked with lacosamide as internal standard. The chromatographic separation was performed on a Fusion (3µm) 50×2.0mm I.D. column with gradient elution of 0.1% (v/v) formic acid in water and 0.1% (v/v) formic acid in acetonitrile at a flow rate of 0.35mL/min. The MS/MS ion transitions were 419.1→343 for nimodipine and 251.1→91 for the internal standard. The linearity was determined from 2.0 to 40.0ng/mL in plasma and 40.0-800.0pg/mL in CSF. The lower limit of quantitation (LLOQ) of nimodipine was 0.4ng/mL in plasma and 40pg/mL in CSF. The mean recovery for nimodipine was ≥75% in plasma and ≥90% in CSF at all three considered concentrations. Intra- and interassay precision and accuracy were ≤15% at all quality control concentrations in plasma and CSF. The method was applied to measure plasma and CSF concentrations of nimodipine in a series of patients with subarachnoid haemorrhage treated with intravenous nimodipine. The present procedure, omitting time-consuming liquid-liquid extraction and drying steps, is faster, simpler and cheaper than published LC-MS/MS analytical methods for nimodipine in plasma and the first validated one for nimodipine in CSF.

Absorption, elimination and cerebrospinal fluid concentrations of nimodipine in healthy beagle dogs receiving human intravenous and oral formulation.

Nimodipine is an L-type calcium channel blocker and is used to treat vasospasm in patients with subarachnoid hemorrhage. Its putative mechanism of action is relaxation of smooth muscle cells in cerebral arteries. In addition, nimodipine may have pleiotropic effects against vasospasm. Systemic hypotension is an adverse effect when patients are treated with oral or intravenous nimodipine. Intracranial administration of nimodipine formulations may produce higher concentration of nimodipine in the cerebrospinal fluid (CSF) than is possible to achieve orally or intravenously, while resulting in lower incidence of systemic hypotension. The aim of this study was to provide information on plasma and CSF levels of nimodipine in beagle dogs as a comparative data for development of experimental intracranial treatment modalities. Plasma levels of nimodipine were measured after current 30 and 60 mg single oral dose of nimodipine (Nimotop(®) 30 mg tablets), a single intravenous bolus 0.72 mg/dog of nimodipine (Nimotop(®) 0.2 mg/ml infusion solution) and CSF levels after 60 mg single oral dose of nimodipine. CSF/Plasma concentration ratio of nimodipine after oral administration of 60 mg at 1 h was 0.013 ± 0.0005. The mean terminal elimination half-life of nimodipine after i.v. bolus dose 0.72 mg was 1.8 h and mean plasma clearance was 40.3 and 3.4 l/h/kg. Absolute bioavailability was 22 %. Maximum plasma concentration and area under the plasma concentration-time curve from time of administration until the last measurable plasma concentration increased in a dose-proportional manner comparing the exposure parameters at oral doses of 30 and 60 mg. Individual variation in the kinetic profile of nimodipine was measured.

Contribution of both olfactory and systemic pathways for brain targeting of nimodipine-loaded lipo-pluronics micelles: in vitro characterization and in vivo biodistribution study after intranasal and intravenous delivery.

Nimodipine (NM) is the only FDA-approved drug for treating subarachnoid hemorrhage induced vasospasm. NM has poor oral bioavailability (5-13%) due to its low aqueous solubility, and extensive first pass metabolism. The objective of this study is to develop radiolabeled NM-loaded LPM and to test its ability prolong its circulation time, reduce its frequency of administration and eventually target it to the brain tissue. NM was radiolabeled with 99mTc by direct labeling method using sodium dithionite. Different reaction conditions that affect the radiolabeling yield were studied. The in vivo pharmacokinetic behavior of the optimum NM-loaded LPM formulation in blood, heart, and brain tissue was compared with NM solution, after intravenous and intranasal administration. Results show that the radioactivity percentage (%ID/g) in the heart of mice following administration of 99mTc-NM loaded LPM were lower compared with that following administration of 99mTc-NM solution, which is greatly beneficial to minimize the cardiovascular side effects. Results also show that the %ID/g in the blood, and brain following intravenous administration of 99mTc-NM-loaded LPM were higher at all sampling intervals compared with that following intravenous administration of 99mTc-NM solution. This would be greatly beneficial for the treatment of neurovascular diseases. The drug-targeting efficiency of NM to the brain after intranasal administration was calculated to be 1872.82%. The significant increase in drug solubility, enhanced drug absorption and the long circulation time of the NM-loaded LPM could be promising to improve nasal and parenteral delivery of NM.

Novel self-assembled nano-tubular mixed micelles of Pluronics P123, Pluronic F127 and phosphatidylcholine for oral delivery of nimodipine: In vitro characterization, ex vivo transport and in vivo pharmacokinetic studies.

Subarachnoid hemorrhage (SAH) is a major cause of death in patients suffering from stroke. Nimodipine (NM) is the only FDA-approved drug for treating SAH-induced vasospasm. However, NM suffers from poor oral bioavailability (5-13%) due to its low aqueous solubility, extensive first pass metabolism and short elimination half-life (1-2h). The objective of this study was to develop NM-loaded Pluronic/phosphatidylcholine/polysorbate 80 mixed micelles (PPPMM) that can solubilize NM in aqueous media even after dilution, prolong its circulation time, improve its bioavailability and eventually help in targeting it to the brain tissue. PPPMM formulations were prepared using the thin film hydration technique, and evaluated for drug payload, solubilization efficiency (SE), micellar size, zeta potential, transmission electron microscopy (TEM) and ex vivo transport through rat intestine. The selected NM-loaded PPPMM, containing PC to Pluronics(®) molar ratio of 75:25, showed a drug payload, SE, micellar size and zeta potential of 1.06 ± 0.03 mg/mL, 99.2 ± 2.01%, 571.5 ± 11.87 nm and -31.2 ± 0.06 mv, respectively. The selected formulation had a much larger hydrophobic core volume for solubilization of NM and exhibited the highest NM transport. TEM micrographs illustrated the formation of highly flexible nano-tubular mixed micelles (NTMM). The in vivo pharmacokinetic study showed greater bioavailability of NM in plasma (232%) and brain (208%) of rats from NM-loaded PPPMM compared to that of the drug solution due to the efficiency of flexible NTMM to enhance absorption of NM from the intestinal mucosa. The significant increase in drug solubility, enhanced drug absorption and the long circulation time of the NTMM could be promising to improve oral and parenteral delivery of NM.

Spectrofluorimetric and micelle-enhanced spectrofluorimetric methods for determination of Felodipine and Nimodipine in pharmaceutical preparations and human plasma.

Rapid, simple and sensitive two spectrofluorimetric methods have been developed for determination of Felodipine (FLD) and Nimodipine (NDP). The first method is based on measuring the native fluorescence of either Felodipine or Nimodipine at 426 nm after excitation at 385 nm. The fluorescence intensity-concentration plots of Felodipine and Nimodipine were rectilinear over the concentration ranges (0.2-3.0) and (0.5-4.0) µg ml(-1), respectively. The second method is based on measuring the fluorescence intensity of the studied drugs in micellar media (0.3% Tween-80) at λex=385 nm and λem=423 nm. In the presence of 0.3% Tween-80, about 1.6-fold and 2.1-fold enhancement can be achieved in the relative fluorescence intensity (RFI) of Felodipine and Nimodipine, respectively. The fluorescence intensity-concentration plots of Felodipine and Nimodipine with Tween-80 were rectilinear over the concentration ranges (0.05-4.0) and (0.1-4.0) µg ml(-1), respectively with determination coefficients (r(2)) of 0.9981 and 0.9990, and limit of quantitation of 0.05 and 0.027µg ml(-1) for FLD and NDP, respectively. The proposed methods were validated according to ICH guidelines and have been successfully applied to the analysis of these drugs in their commercial tablets with high accuracy (97.6-98.8±0.50-1.42%, n=5). The high sensitivity of micellar method permits its application for determination of the cited drugs in spiked human plasma with % recovery (91.9-106.6±0.66-1.7%, n=6).

Serum levels of nimodipine in enteral and parenteral administration in patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND: The aim of this study was to evaluate serum nimodipine concentrations in patients with aneurysmal subarachnoid hemorrhage (SAH) after parenteral therapy and a following course of enteral administration. METHODS: SAH patients were treated with intravenous nimodipine (2 mg/h) during the 1st week after hemorrhage, and on day 8, we switched over to enteral administration (60 mg/4 h), either orally or by gavage. Serum nimodipine concentrations were measured on days 3, 5, 8, 9 and 12. Area under the curve (AUC) was calculated during parenteral and enteral therapy. The data of 15 patients were analyzed retrospectively. RESULTS: In this study, 157 blood samples were obtained. In seven samples, during the administration by gavage to two patients with high-grade SAH, the serum nimodipine concentrations were negligible. The AUC values during parenteral administration (median 149.3 ng-h/ml) were significantly higher than during oral administration on days 9 (median 92.1 ng-h/ml) and 12 (median 44.1 ng-h/ml) in seven patients (p = 0.030 and p = 0.016, respectively). The AUC values during parenteral administration were significantly higher than during administration by gavage on day 9 in eight patients (median 87.9 and 34 ng-h/ml, respectively, p = 0.001). The AUC values during enteral administration were higher in patients who received nimodine orally than in those who received it by gavage (median 52.3 and 23.1 ng-h/ml, respectively, p = 0.006). CONCLUSIONS: Enteral administration of nimodipine showed lower bioavailability during the 2nd week after SAH compared to parenteral application during the 1st week. Negligible serum concentrations were even expected when nimodipine was given by gavage in patients with high-grade SAH, thus suggesting that parenteral administration may be the better route in these patients.

Drug-induced changes to the vertebral endplate vasculature affect transport into the intervertebral disc in vivo.

Intervertebral disc health is mediated in part by nutrient diffusion from the microvasculature in the adjacent subchondral bone. Evidence suggests that a reduction in nutrient diffusion contributes to disc degeneration, but the role of the microvasculature is unclear. The purpose of this study was to induce changes in the endplate microvasculature in vivo via pharmaceutical intervention and then correlate microvasculature characteristics to diffusion and disc health. New Zealand white rabbits were administered either nimodipine (to enhance microvessel density) or nicotine (to diminish microvessel density) daily for 8 weeks compared to controls. Trans-endplate diffusion and disc health were quantified using post-contrast enhanced magnetic resonance imaging (MRI). Histology was utilized to assess changes to the subchondral vasculature. Results indicate that nimodipine increased vessel area and vessel-endplate contact length, causing a significant increase in disc diffusion. Surprisingly, nicotine caused increases in vessel number and area but did not alter diffusion into the disc. The drug treatments did affect the microvasculature and diffusion, but the relationship between the two is complex and dependent on multiple factors which include vessel-endplate distance, and vessel-endplate contact length in addition to vessel density. Our data suggest that drugs can modulate these factors to augment or diminish small molecule transport.

Effect of natural borneol on the pharmacokinetics and distribution of nimodipine in mice.

The purpose of this study was to investigate the effect of natural borneol (NB) on the pharmacokinetics and distribution of nimodipine in mice. A single dose of nimodipine was administered intravenously (2 mg/kg) to mice pretreated with NB (250 mg/kg) or vehicle. Blood as well as brain, liver, and kidney tissue samples were collected at 5, 10, 20, 40, and 60 min post-dose nimodipine. The concentrations of nimodipine in plasma and tissues were determined by ultra performance liquid chromatography (UPLC) coupled with UV detection, and the pharmacokinetic parameters were calculated based on non-compartmental analysis. NB increased the plasma AUC5-60 min by 26 % compared to the vehicle. In addition, brain concentrations of nimodipine in NB-treated mice were significantly higher than those in control mice with the increased AUC5-60 min by 30 %. In liver and kidney, NB also caused 26 and 47 % increase in AUC5-60 min, respectively. These results implicated that NB may inhibit the metabolism or elimination of nimodipine and enhance its distribution in brain and kidney tissue.

Determination of limonin in dog plasma by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study.

A highly sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of limonin in beagle dog plasma using nimodipine as internal standard. The analyte and internal standard (IS) were extracted with ether followed by a rapid isocratic elution with 10 mm ammonium acetate buffer-methanol (26:74, v/v) on a C18 column (150 × 2.1 mm i.d.) and subsequent analysis by mass spectrometry in the multiple reaction monitoring mode. The precursor to product ion transitions of m/z 469.4 → 229.3 and m/z 417.2 → 122.0 were used to measure the analyte and the IS. The assay was linear over the concentration range of 0.625-100 ng/mL for limonin in dog plasma. The lower limit of quantification was 0.312 ng/mL and the extraction recovery was >90.4% for limonin. The inter- and intra-day precision of the method at three concentrations was less than 9.9%. The method was successfully applied to pharmacokinetic study of limonin in dogs.