Bioavailability and Pharmacokinetics of Isradipine after Oral and Intravenous Administration: Half-Life Shorter than Expected?

Christensen, Hanne; Antonsen., Kristian; Simonsen, Knud; Lindekær, A. L.; Bonde, Jan; Angelo, Helle R.; Kampmann, Jens P.

doi:10.1034/j.1600-0773.2000.d01-32.x

Cited by 20 publications

(12 citation statements)

References 11 publications

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“…Our preliminary studies have clearly shown the superior effects of isradipine over nimodipine in vitro [29]. We also predict that the brain bioavailability of therapeutic doses of isradipine is superior to that of nimodipine, as bioavailability studies in animals generally support this assertion [89, 90]. …”

Section: Calcium Channel Blockers To Break the Nexus Of Toxicitymentioning

confidence: 83%

“…In the past three decades, several bioanalytical methods (radioactive labeling, gas chromatography, high pressure liquid chromatography) have been developed for assessing isradipine pharmacokinetics and pharmacodynamics in animal and human tissues [6, 86, 89, 90, 102, 103]. The most important discovery from these early methods is that isradipine undergoes extensive first-pass metabolism and nearly 90% of orally administered isradipine is absorbed in the digestive tract, limiting its bioavailability to about 17-28% in plasma.…”

Section: Bioavailability Of Calcium Channel Blockersmentioning

confidence: 99%

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Calcium channel blocking as a therapeutic strategy for Alzheimer's disease: The case for isradipine

Anekonda

Quinn

2011

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

117

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Alzheimer’s disease is the most devastating neurodegenerative disorder in the elderly, yet treatment options are severely limited. The drug development effort to modify Alzheimer’s disease pathology by intervention at beta amyloid production sites has been largely ineffective or inconclusive. The greatest challenge has been to identify and define downstream mechanisms reliably predictive of clinical symptoms. Beta amyloid accumulation leads to dysregulation of intracellular calcium by plasma membrane L-type calcium channels located on neuronal somatodendrites and axons in the hippocampus and cortex. Paradoxically, L-type calcium channel subtype Cav1.2 also promotes synaptic plasticity and spatial memory. Increased intracellular calcium modulates amyloid precursor protein processing and affects multiple downstream pathways including increased hyperphosphorylated tau and suppression of autophagyIsradipine is a Federal Drug Administration-approved dihydropyridine calcium channel blocker that binds selectively to Cav1.2 in the hippocampus. Our studies have shown that isradipine in vitro attenuates beta amyloid oligomer toxicity by suppressing calcium influx into cytoplasm and by suppressing Cav1.2 expression. We have previously shown that administration of isradipine to triple transgenic animal model for Alzheimer’s disease was well-tolerated. Our results further suggest that isradipine became bioavailable, lowered tau burden, and improved autophagy function in the brain. A better understanding of brain pharmacokinetics of calcium channel blockers will be critical for designing new experiments with appropriate drug doses in any future clinical trials for Alzheimer’s disease. This review highlights the importance of Cav1.2 channel overexpression, the accumulation of hyperphosphorylated tau and suppression of autophagy in Alzheimer’s disease and modulation of this pathway by isradipine.

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Section: Calcium Channel Blockers To Break the Nexus Of Toxicitymentioning

confidence: 83%

Section: Bioavailability Of Calcium Channel Blockersmentioning

confidence: 99%

Calcium channel blocking as a therapeutic strategy for Alzheimer's disease: The case for isradipine

Anekonda

Quinn

2011

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

117

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“…However, none of them have studied the pharmacokinetics at a dose of 2.5 mg. In addition, Christensen et al (2000) found that the half-life of isradipine reported in different studies varied significantly. The terminal half-life of isradipine after an oral dose from Fitton and Benfield (1990) was about 8.8 h, while Christensen observed a significantly shorter half-life (2.5 h) following intravenous isradipine in patients with pregnancyinduced hypertension.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic properties of isradipine after single‐dose and multiple‐dose oral administration in Chinese volunteers: a randomized, open‐label, parallel‐group phase I study

Wang

Jin

Wang

et al. 2013

Biomedical Chromatography

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Isradipine could be used for the treatment of high blood pressure or Parkinsonism, yet the study on pharmacokinetics (PK) of isradipine is lacking in the Chinese population. The current study aims to assess the dose proportionality, pharmacokinetics and gender effect of isradipine following oral single and multiple doses in Chinese subjects. A randomized, open-label, parallel-group trial was conducted in 30 healthy Chinese volunteers. Subjects randomly received a single dose of 2.5, 5 or 10 mg, and multiple doses (2.5 mg) of isradipine. Blood samples were collected pre-dose (0 h) and 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, 36 and 48 h post-dose. Isradipine was rapidly absorbed with the time to maximum concentration <1.27 h for all dosage groups. The maximum concentrations were 2.46, 5.34, 10.93 and 3.32 ng/mL and area under the concentration-time curve from time zero to the last time point (AUClast ) were 7.05, 12.58, 24.68 and 5.31 ng/ml · h for the 2.5, 5 and 10 mg single-dose and 2.5 mg multiple-dose groups, respectively. The half-life ranged from 5.76 to 7.94 h. The maximum concentration and AUC were found to increase linearly and dose-dependently for isradipine. No statistical gender differences were found. These findings indicated that the pharmacokinetic parameters of isradipine in Chinese population were dose-proportional and predictable over a range of 2.5-10 mg isradipine oral doses.

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“…Isradipine, a calcium antagonist, has low oral BA due to its poor water-solubility and extensive first-pass metabolism [98]. Bobbala et al showed a 2.0-fold increase of oral BA in rats with proliposomes consisted with hydrogenated soybean phosphatidylcholine (HSPC) and CH (1:1) compared to the isradipine suspension in 0.5% sodium CMC [25].…”

Section: Isradipinementioning

confidence: 99%

Liposomes for Enhanced Bioavailability of Water-Insoluble Drugs: In Vivo Evidence and Recent Approaches

Lee

2020

Pharmaceutics

155

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It has been known that a considerable number of drugs in clinical use or under development are water-insoluble drugs with poor bioavailability (BA). The liposomal delivery system has drawn attention as one of the noteworthy approaches to increase dissolution and subsequently absorption in the gastrointestinal (GI) tract because of its biocompatibility and ability to encapsulate hydrophobic molecules in the lipid domain. However, there have been several drawbacks, such as structural instability in the GI tract and poor permeability across intestinal epithelia because of its relatively large size. In addition, there have been no liposomal formulations approved for oral use to date, despite the success of parenteral liposomes. Nevertheless, liposomal oral delivery has resurged with the rapid increase of published studies in the last decade. However, it is discouraging that most of this research has been in vitro studies only and there have not been many water-insoluble drugs with in vivo data. The present review focused on the in vivo evidence for the improved BA of water-insoluble drugs using liposomes to resolve doubts raised concerning liposomal oral delivery and attempted to provide insight by highlighting the approaches used for in vivo achievements.Pharmaceutics 2020, 12, 264 2 of 30 However, there have been several drawbacks to be overcome, such as instability in the GI tract and poor permeability across the intestinal epithelia because of liposomes' relatively large size [8]. Moreover, it seemed that liposomal oral delivery was faltering during 1980s due to some disappointing results for insulin [9]. However, liposomal oral delivery resurged with a rapid increase in the number of papers published, as shown in Pubmed search results, mainly due to various advanced modification technologies, even though liposomal oral delivery-related papers account for only 5-6% of the total number of liposomes-related studies (Figure 1). In addition, there was an encouraging meta-analysis report in which phospholipid-based solid formulations were analyzed as being effective for BA enhancement [10]. Although liposomal delivery does not seem to achieve satisfactory improvement of oral BA for peptides and protein drugs yet, it looks more promising for oral delivery of hydrophobic drugs because liposomes can solubilize poorly water-soluble drugs, protect the drug from degradation in the GI tract and enhance permeability through the epithelial cell membrane, consequently increasing oral BA. However, most published papers performed in vitro studies only, thus lacking in vivo pharmacokinetic results. The present review focuses on the in vivo evidence for the improved BA of water-insoluble drugs and highlights the approaches used for in vivo achievements.

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Bioavailability and Pharmacokinetics of Isradipine after Oral and Intravenous Administration: Half-Life Shorter than Expected?

Cited by 20 publications

References 11 publications

Calcium channel blocking as a therapeutic strategy for Alzheimer's disease: The case for isradipine

Calcium channel blocking as a therapeutic strategy for Alzheimer's disease: The case for isradipine

Pharmacokinetic properties of isradipine after single‐dose and multiple‐dose oral administration in Chinese volunteers: a randomized, open‐label, parallel‐group phase I study

Liposomes for Enhanced Bioavailability of Water-Insoluble Drugs: In Vivo Evidence and Recent Approaches

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