Pharmacokinetics Of Nimodipine Research Articles

Nimodipine Pharmacokinetic Variability in Various Patient Populations.

Nimodipine has been shown to improve outcomes following aneurysmal subarachnoid hemorrhage. Guidelines recommend that all patients receive a fixed dose of oral nimodipine for 21 days. However, pharmacokinetic studies have suggested variability of nimodipine pharmacokinetics in subarachnoid hemorrhage and in other patient populations. The clinical relevance of such variability is unknown. Therefore, the objective of the present review is, first, to conduct a literature review and summarize nimodipine pharmacokinetic data and sources of variability in various patient groups. Second, to determine if there is any evidence reporting an association between nimodipine exposure and clinical outcomes in patients with subarachnoid hemorrhage. A systematic literature search was performed in MEDLINE and EMBASE. The following keywords were used: (“nimodipine” OR “nymalize” OR “nimotop”) AND (“pharmacokinetic*”, OR “PK”). The search results were limited to English language and human studies. A large interpatient variability in nimodipine pharmacokinetics has been reported. Patient-specific factors that had an influence on pharmacokinetic parameters are age, comorbidities, variabilities in metabolism due to genetic polymorphism and co-administered medications, as well as nimodipine administration technique. The association between nimodipine exposure and clinical outcomes remains unclear and data available are too scarce to reach a firm conclusion. Here, we present a narrative review with a systematic literature search discussing nimodipine pharmacokinetic variability in various patient populations. It is not clear if minimal or lack of systemic exposure to nimodipine denies its benefit and contributes to worsening outcomes in patients with subarachnoid hemorrhage. Further studies are needed to determine if such an association exists.

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 5.0mg/kg io and iv and 10.0mg/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 5min 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.

Nimodipine pharmacokinetics after intraventricular injection of sustained-release nimodipine for subarachnoid hemorrhage.

The objective of this study was to measure the concentration of nimodipine in CSF and plasma after intraventricular injection of a sustained-release formulation of nimodipine (EG-1962) in patients with aneurysmal subarachnoid hemorrhage (SAH). Patients with SAH repaired by clip placement or coil embolization were randomized to EG-1962 or oral nimodipine. Patients were classified as grade 2-4 on the World Federation of Neurosurgical Societies grading scale for SAH and had an external ventricular drain inserted as part of their standard of care. Cohorts of 12 patients received 100-1200 mg of EG-1962 as a single intraventricular injection (9 per cohort) or they remained on oral nimodipine (3 per cohort). Plasma and CSF were collected from each patient for measurement of nimodipine concentrations and calculation of maximum plasma and CSF concentration, area under the concentration-time curve from day 0 to 14, and steady-state concentration. Fifty-four patients in North America were randomized to EG-1962 and 18 to oral nimodipine. Plasma concentrations increased with escalating doses of EG-1962, remained stable for 14 to 21 days, and were detectable at day 30. Plasma concentrations in the oral nimodipine group were more variable than for EG-1962 and were approximately equal to those occurring at the EG-1962 800-mg dose. CSF concentrations of nimodipine in the EG-1962 groups were 2-3 orders of magnitude higher than in the oral nimodipine group, in which nimodipine was only detected at low concentrations in 10% (21/213) of samples. In the EG-1962 groups, CSF nimodipine concentrations were 1000 times higher than plasma concentrations. Plasma concentrations of nimodipine similar to those achieved with oral nimodipine and lasting for 21 days could be achieved after a single intraventricular injection of EG-1962. The CSF concentrations from EG-1962, however, were at least 2 orders of magnitude higher than those with oral nimodipine. These results supported a phase 3 study that demonstrated a favorable safety profile for EG-1962 but yielded inconclusive efficacy results due to notable differences in clinical outcome based on baseline disease severity.Clinical trial registration no.: NCT01893190 (ClinicalTrials.gov).

Pharmacokinetics of Nimodipine after Intraocular Administration in Rats

Objective To explore the pharmacokinetics of nimodipine in plasma of rats after intraocular administration.Methods Totally 135 SD rats were randomly divided into three groups according to drug administration routes:intraocular(io group),intravenous (iv group),and intragastric (ig group). The doses were 5.0 mg/kg for IO and IV groups and 10.0 mg/kg for IG group. The serum nimodipine level was analyzed by high performance liquid chromatography. The main pharmacokinetic parameters were calculated and compared.Results The pharmacokinetic parameters in io group were as follows:Cmax:0.52 mg/ml;tmax:5.0 min;and AUC0-t:21.10 mg/(ml·min). The main pharmacokinetic parameters in iv group were as follows:Cmax:3.62 mg/ml;and AUC0-t:52.58 mg/(ml·min). The main pharmacokinetic parameters in ig group were as follows:Cmax:0.20 mg/ml;tmax:5.0 min;and AUC0-t:5.98 mg/(ml·min).Conclusions Nimodipine is rapidly absorbed after io administration,and the ophthalmic formulation has a higher bioavailability than the oral solution. Therefore,the io route may help to improve the treatment effectiveness of cardiovascular diseases.

Effects of pravastatin on the pharmacokinetic parameters of nimodipine after oral and intravenous administration in rats: Possible role of CYP3A4 inhibition by pravastatin

Objective:The aim of this study was to investigate the effects of pravastatin on the pharmacokinetics of nimodipine in rats.Materials and Methods:The effect of pravastatin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was evaluated. Nimodipine was administered to rats intravenously (3 mg/kg) and orally (12 mg/kg) with pravastatin (0.3 and 1 mg/kg).Results:Pravastatin inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibition concentration (IC50) of 14 µM. Compared with the oral control group, the area under the plasma concentration-time curve (AUC0-∞) of nimodipine was increased significantly. Consequently, the absolute bioavailability (AB) of nimodipine with pravastatin (1 mg/kg) was 31.1%, which was significantly enhanced compared with the oral control group. Moreover, the relative bioavailability (RB) of nimodipine was 1.12- to 1.31-fold greater than that of the control group.Conclusions:The enhanced oral bioavailability of nimodipine might be mainly due to inhibition of the CYP3A-mediated metabolism of nimodipine in the small intestine and/or in the liver and due to reduction of the total body clearance rather than both to inhibition of the P-gp efflux transporter in the small intestine and reduction of renal elimination of nimodipine by pravastatin. The increase in the oral bioavailability of nimodipine with pravastatin should be taken into consideration of potential drug interactions between nimodipine and pravastatin.

Effects of Kaempferol, an Antioxidant, on the Bioavailability and Pharmacokinetics of Nimodipine in Rats

The aim of this study was to investigate the effects of kaempferol on the pharmacokinetics of nimodipine in rats. Nimodipine and kaempferol interact with cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), and the increase in the use of health supplements may result in kaempferol being taken concomitantly with nimodipine as a combination therapy to treat orprevent cardiovascular disease. The effect of kaempferol on P-gp and CYP3A4 activity was evaluated and Pharmacokinetic parameters of nimodipine were determined in rats after an oral (12 mg/kg) and intravenous (3 mg/kg) administration of nimodipine to rats in the presence and absence of kaempferol (0.5, 2.5, and 10 mg/kg). Kaempferol inhibited CYP3A4 enzyme activity in a concentration-dependent manner with 50% inhibition concentration (IC50) of 17.1 µM. In addition, kaempferol significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ ADR cells overexpressing P-gp. Compared to the oral control group, the area under the plasma concentration-time curve (AUC0-∞) and the peak plasma concentration (Cmax) of nimodipine significantly increased, respectively. Consequently, the absolute bioavailability of nimodipine in the presence of kaempferol (2.5 and 10 mg/kg) was 29.1-33.3%, which was sig- nificantly enhanced compared to the oral control group (22.3%). Moreover, the relative bioavailability of nimodipine was 1.30- to 1.49-fold greater than that of the control group. The pharmacokinetics of intravenous nimodipine was not affected by kaempferol in contrast to those of oral nimodipine. Kaempferol significantly enhanced the oral bioavailability of nimo- dipine, which might be mainly due to inhibition of the CYP3A4-mediated metabolism of nimodipine in the small intestine and /or in the liver and to inhibition of the P-gp efflux transporter in the small intestine by kaempferol. The increase in oral bioavailability of nimodipine in the presence of kaempferol should be taken into consideration of potential drug interactions between nimodipine and kaempferol. Key wordsNimodipine, Kaempferol, Pharmacokinetics, Bioavailability, P-gp, CYP3A4, Rats Nimodipine is a dihydropyridine calcium channel blocker that has been shown to selectively dilate cerebral arteries and increase cerebral blood flow in animals and humans (Kazda et al., 1982). Its major therapeutic indication is for the prevention and treatment of delayed ischemic neurological disorders that often occur in patients with subarachnoid hemorrhages (Epstein and Loutzenhister, 1990; Scholz, 1997). Nimodipine is rapidly absorbed after oral administration and is widely dis- tributed throughout the body. Orally administered nimodipine is subject to an extensive first-pass hepatic metabolism from the portal circulation, resulting in a low systemic bioavail- ability (Maruhn et al., 1985; Suwelack et al., 1985). Usually only the parent compound is active and most of the metabolic steps involve reactions catalyzed by cytochrome P450 (CYP) enzymes. CYP enzymes have been shown to catalyze pyridine

Effects of the antioxidant baicalein on the pharmacokinetics of nimodipine in rats: a possible role of P-glycoprotein and CYP3A4 inhibition by baicalein

The reduced bioavailability of nimodipine after oral administration might not only be due to the metabolizing enzyme cytochrome P450 3A4(CYP3A4) but also to the P-glycoprotein efflux transporter in the small intestine. The aim of this study was to investigate the effects of baicalein on the pharmacokinetics of nimodipine in rats. The effect of baicalein on P-glycoprotein and CYP3A4 activity was evaluated. A single dose of nimodipine was administered intravenously (3mg/kg) and orally (12mg/kg) to rats in the presence and absence of baicalein (0.4, 2 and 8mg/kg). Baicalein inhibited CYP3A4 enzyme activity in a concentration-dependent manner, with a 50% inhibition concentration (IC50) of 9.2µM. In addition, baicalein significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-glycoprotein. Baicalein significantly altered the pharmacokinetics of orally administered nimodipine. Compared to the oral control group given nimodipine alone, the area under the plasma concentration-time curve (AUC0–∞) and the peak plasma concentration (Cmax) of nimodipine significantly increased (p < 0.05 for 2mg/kg; p < 0.01 for 8mg/kg). Consequently, the absolute bioavailability of nimodipine in the presence of baicalein (2 and 8mg/kg) was 31.0–35.3%, which was significantly enhanced (p < 0.05 for 2mg/kg; p < 0.01 for 8mg/kg) compared to the oral control group (22.3%). Moreover, the relative bioavailability of nimodipine was 1.39- to 1.58-fold greater than that of the control group. The pharmacokinetics of intravenous nimodipine were not affected by baicalein in contrast to those of oral nimodipine. Baicalein significantly enhanced the oral bioavailability of nimodipine, which may be mainly due to inhibition of the CYP3A4-mediated metabolism of nimodipine in the small intestine and/or in the liver and the inhibition of the P-glycoprotein efflux pump in the small intestine by baicalein. The increase in oral bioavailability of nimodipine in the presence of baicalein should be taken into consideration as a potential drug interaction between nimodipine and baicalein.

Early-phase pharmacokinetics of enteral and parenteral nimodipine in patients with acute subarachnoid haemorrhage – a pilot study

The pharmacokinetics of nimodipine following enteral administration in the early phase after subarachnoid haemorrhage (SAH) has not been described. If a sufficient absorption could be achieved with enterally administered nimodipine, this would be more feasible dosage form and result in a significant reduction in pharmaceutical costs given that the parenteral formulation of nimodipine currently used is tenfold more expensive than the enteral formulation. This was a pilot study in which 17 patients with aneurysmal SAH were randomly assigned to receive nimodipine within 24 h after initial bleeding either as an 60 mg tablet/suspension at 4-h intervals, or as a continuous intravenous infusion of 2 mg/h. Serum nimodipine concentrations were measured during the 4 h following the first dose, and at 24 and 72 h on a validated gas chromatography mass spectrometer (GC-MS). Nimodipine AUC values (expressed in mug min/ml) were lower in the eight SAH patients receiving enteral nimodipine [AUC(0-4) range: 0.13-5.4 (median: 0.32); AUC(24-28) range: 0.16-6.1 (0.71); AUC(72-76) range: 0.47-20.6 (1.9)] than in the nine patients receiving a continuous intravenous infusion of nimodipine [AUC(0-4) range: 2.4-4.9 (3.4), p=0.059; AUC(24-28) range: 4.7-10.3 (7.3), p=0.001; AUC(72-76) range: 3.4-8.6 (6.9), p=0.001]. In three of five good-grade SAH patients receiving nimodipine tablets the AUC values were comparable to those of the intravenous administration, but in two good-grade patients with tablets and in all three poor-grade (Hunt&Hess, grade IV) SAH patients receiving the suspension, the rate and extent of nimodipine absorption was negligible. This pilot study indicates that the rate and extent of nimodipine absorption following enteral administration in some acute SAH patients could be negligible, and this may particularly be the case in patients with a decreased level of consciousness.

The Pharmacokinetics of Nimodipine After Oral Administration in Rabbits with Hepatic Failure

The pharmacokinetics of nimodipine, following a single 16 mg/kg oral dose, was investigated in rabbits with hepatic failure induced by 0.5 mL/kg (mild), 1.0 mL/kg (moderate) and 2.0 mL/kg (severe) of carbon tetrachloride : olive oil = 20 : 80, v/v). The plasma concentrations of nimodipine were determined by a high performance liquid chromatographic assay. The levels of sGOT and sGPT in rabbits with mild , moderate and severe hepatic failure were significantly increased compared to the control . The area under the plasma concentration-time curve (AUC) of nimodipine was significantly increased in mild , moderate and severe carbon tetrachloride-induced hepatic failure rabbits compared to the control (100%) rabbits. The volume of distribution and the total body clearance of nimodipine were significantly decreased in all hepatic failure groups. The elimination rate constant of nimodipine was significantly decreased in moderate and severe carbon tetrachloride-induced hepatic failure rabbits. There was a correlation between sGOT (y= 1.01x+241, r=0.993) or sGPT (y=0.92x +243, r=0.997) value and the AUC of nimodipine in the rabbits with hepatic failure. These findings suggest that the hepatic metabolism of nimodipine was inhibited by carbon tetrachloride-induced hepatic failure rabbits, resulting in the decrese in and of nimodipine in the rabbits with mild, moderate and severe hepatic failure.

Effect of P-glycoprotein inhibitors erythromycin and cyclosporin A on brain pharmacokinetics of nimodipine in rats.

Effect of P-glycoprotein (P-gp) inhibitors erythromycin (Ery) and cyclosporin A(CsA) on brain pharmacokinetics of nimodipine (NMD) in rats was studied. NMD concentrations in rat plasma and brain were determined after iv 2 mg/kg NMD alone, co-administration with Ery and CsA, respectively. It was found that concentrations of NMD in plasma of the three groups had a little difference, but brain concentrations of NMD in rats co-administrated with Ery and CsA were significantly higher than those in rats NMD alone. Significances of NMD in rat brain were found at 20, 40, 60 and 90 min after iv NMD. The brain T(1/2) in rat treated with ery(75.0 min) and CsA(79.0 min) were larger than that (44.2 min) in rats NMD alone. The results indicated that P-gp inhibitors Ery and CsA may increase concentration in rat brain by inhibiting elimination of NMD from brain.

Nimodipine: drug pharmacokinetics and plasma adenosine levels in patients affected by cerebral ischemia.

Nimodipine is a dihydropyridine calcium channel blocker used in the treatment of ischemic damage in subarachnoid hemorrhage. Recent investigations have shown that it is able to inhibit adenosine transport in human red blood cells and parietal cortex neurons. In this study we investigated the pharmacokinetics of nimodipine and the effect on plasma adenosine levels in patients affected by cerebral ischemia. Twelve patients with cerebral ischemia (9 men and 3 women; mean age, 68.8 +/- 11.2 years; mean weight, 67.9 +/- 9.3 kg) were admitted to the study. They received nimodipine intravenously (a bolus of 0.03 mg/kg) and orally (single doses of 30, 60, and 90 mg) during different sessions. Blood samples for adenosine and nimodipine were collected at fixed intervals up to 480 minutes. Adenosine and nimodipine plasma levels were detected by HPLC methods. Both the intravenous and oral administrations induced a statistically significant increase in plasma adenosine levels (P <.001), which appeared to be related to the dose and route of drug administration. In particular, a 67.8% increase was observed after intravenous administration, and increases of 28.9%, 43.6%, and 60.2% were observed after 30 mg, 60 mg, and 90 mg of nimodipine, respectively. The pharmacokinetic parameters of nimodipine after intravenous administration were as follows: peak concentration (C(max)), 319.6 +/- 38.9 ng/mL at the first sampling time; area under the curve (AUC), 239 +/- 25 ng. h/mL; and terminal half-life, 3.12 +/- 0.97 hours. After oral administration, the drug kinetics was linear in the administered dose range and the pharmacokinetic parameters were as follows: C(max)(30 mg), 46.1 +/- 5.8 ng/mL; C(max)(60 mg), 81.7 +/- 14.6 ng/mL; C(max)(90 mg), 131.6 +/- 16.3 ng/mL; AUC(30 mg), 119 +/- 25 ng. h/mL; AUC(60 mg), 256 +/- 48 ng. h/mL; and AUC(90 mg), 389 +/- 54 ng. h/mL. The half-life was similar to the values observed after intravenous administration, whereas the bioavailability ranged between 2% and 5.9%. Our data indicate that the administration of nimodipine induces an increase in plasma adenosine levels, and we hypothesize that the drug activity could be associated, at least partially, with adenosine mediation.

Clinical pharmacokinetics of drugs for Alzheimer's disease.

Pharmacological treatment of patients with Alzheimer's disease is becoming more important, as evidenced by the number of drugs being developed in different countries. It has been shown in the majority of clinical trials that cholinesterase inhibitors, such as tacrine (tetrahydroaminoacridine), are able to induce beneficial effects in cognition and memory. Tacrine, like most of the other oral antidementia agents, is rapidly absorbed from the gastrointestinal tract. It is excreted mainly through the kidney, with a terminal elimination half-life of about 3 hours. Tacrine has nonlinear pharmacokinetics and there are large interindividual differences in pharmacokinetic parameters after oral, intravenous and rectal administration. A positive relationship between cognitive changes and plasma tacrine concentrations has been recently described. Similarly, velnacrine exhibits evidence of nonlinearity in some pharmacokinetic parameters, but renal excretion is a minor route of elimination for this drug. Pharmacokinetic data pertaining to eptastigmine, a third cholinesterase inhibitor, is more limited. However, the drug is rapidly distributed to the tissues after oral administration and readily enters the central nervous system, where it can be expected to effectively inhibit acetylcholinesterase in the brain for a prolonged period. Pharmacokinetic data for the nootropic agents are more limited. However, of the 3 agents reviewed only pramiracetam penetrates the central nervous system (CNS) poorly. Indeed, oxiracetam crosses the blood-brain barrier and persists for longer in the CNS than in the serum. Selegiline (deprenyl), a neuroprotective agent, is readily absorbed from gastrointestinal tract. It is metabolised mainly in the liver, and to a minimal extent in the lung or kidneys. The steady-state concentrations of metabolites in the cerebrospinal fluid (CSF) and serum are very similar, reflecting their easy penetration into the CNS. Idebenone, another neuroprotective agent, likewise is rapidly absorbed and achieves peak concentrations in the brain comparable to those in plasma. Similarly, CSF concentrations of metabolites of ST 200 (acetyl-L-carnitine) parallel those in plasma, suggesting that they easily cross the blood-brain-barrier. Gangliosides (GM1) can be given intramuscularly or subcutaneously, but the latter route of administration provides a concentration 50% higher both in the serum and the ganglioside fraction. However, because of its longer elimination, the intramuscular route is the best form of administration when the brain is the target organ for the treatment. Absorption of nimodipine is quite rapid. The pharmacokinetics of nimodipine during multiple-dose treatment have not been studied extensively; however, the drug does not appear to accumulate during repeated administration of standard doses.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetics of nimodipine in multimorbid elderly patients with chronic brain failure

Twenty-one elderly patients with chronic brain failure received a single 30 mg oral dose of the calcium channel blocker nimodipine followed by two weeks of 30 mg three times a day (t.i.d.) administration. The aim of this study was to assess if drug accumulation occurred in our frail elderly subjects under this dose regimen. Plasma concentrations of nimodipine and three main metabolites were determined by gas chromatography. During the 2-week period we did not find significant changes in peak plasma concentrations and corresponding areas under the plasma concentration—time curves. Trough nimodipine plasma concentrations before administration of the morning dose were similar on days 7 and 14. Therefore, no evidence of drug accumulation was found. Blood pressure and heart rate remained stable throughout the study period and no adverse effects were observed. During the study period, there was a decline in the proportion of patients who complained about dizziness and insomnia. Overall, our data suggest that there is no need to alter the usual adult dose of nimodipine if this drug is administered to multimorbid frail elderly patients suffering from chronic brain failure.

Influence of the H2-receptor antagonists cimetidine and ranitidine on the pharmacokinetics of nimodipine in healthy volunteers

A possible interaction between the calcium antagonist nimodipine and the H2-receptor antagonists cimetidine and ranitidine has been investigated in two separate studies in healthy subjects. In eight young volunteers the concomitant administration of nimodipine 30 mg t.i.d. and cimetidine 1000 mg/d for 7 days led to a significant increase of the relative bioavailability of nimodipine. The changes in the pharmacokinetic parameters were not accompanied by discernible haemodynamic effects or any change in the tolerability of nimodipine. There was no evidence of any significant change in the steady-state pharmacokinetics of nimodipine during five days of combined treatment with 30 mg t.i.d. nimodipine and ranitidine 300 mg/d given as single morning dose to twelve healthy, elderly subjects. Analysis of haemodynamics, clinical chemistry and tolerance also did not reveal any difference between the two treatment periods.

Differential effects of valproic acid and enzyme‐inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients.

1. The single dose pharmacokinetics of orally administered nimodipine (60 mg) were investigated in normal subjects and in two groups of epileptic patients receiving chronic treatment with hepatic microsomal enzyme-inducing anticonvulsants (carbamazepine, phenobarbitone or phenytoin) and sodium valproate, respectively. 2. Compared with the values found in the control group, mean areas under the plasma nimodipine concentration curve were lowered by about seven-fold (P less than 0.01) in patients taking enzyme-inducing anticonvulsants and increased by about 50% (P less than 0.05) in patients taking sodium valproate. 3. Nimodipine half-lives were shorter in enzyme-induced patients than in controls (3.9 +/- 2.0 h vs 9.1 +/- 3.4 h, means +/- s.d., P less than 0.01), but this difference could be artifactual since in the patients drug concentrations declined rapidly below the limit of assay, thus preventing identification of a possible slower terminal phase. In valproate-treated patients, half-lives (8.2 +/- 1.8 h) were similar to those found in controls.

Plasma concentrations and haemodynamic effects of nimodipine in patients resuscitated after cardiac arrest.

As the pharmacokinetics of a drug may be altered in haemodynamically compromised patients, the plasma concentrations and haemodynamic effects of the calcium entry blocker nimodipine have been examined in patients resuscitated after out-of-hospital cardiac arrest. In 7 patients nimodipine was infused at increasing rates up to 30 micrograms.kg-1.h-1. The plasma concentrations increased with increasing dose; at the highest dose a mean steady-state plasma concentration of 22.1 ng.ml-1 was obtained, and the mean plasma clearance was 1.41.kg-1.h-1. There were no marked changes in mean arterial blood pressure or heart rate. In 9 other patients nimodipine was given as a bolus infusion of 10 micrograms.kg-1 over 3 min, followed by a continuous infusion of 30 micrograms.kg-1.h-1. A mean steady-state plasma concentration of 17.6 ng.ml-1 was obtained and the mean plasma clearance was 1.91.kg-1.h-1. Heart rate did not change significantly, but the mean arterial blood pressure fell. The data indicate that in patients resuscitated after cardiac arrest, the pharmacokinetics of nimodipine are not markedly different from patients with other conditions, e.g. subarachnoid haemorrhage. However, if a loading dose is given to obtain a steady-state concentration sooner, there will be a fall in arterial blood pressure.