Table 2.
Properties and routes of administration of selected drugs for epilepsy, stroke, cancer and traumatic brain injury.
| Drug Name and Classification | Properties | Route of Administration | Potential Challenges | References |
|---|---|---|---|---|
| Anti-seizure medications | ||||
| Carbamazepine | Prolonged Tmax (6–12 h), insoluble, plasma half-life 35 h |
Oral, rectal | Rectal administration caused irritating and cathartic effects, CYP3A4induction |
[149,150] |
| Gabapentin | Soluble, plasma half-life 5–7 h |
Oral | Potential drug interactions | [151,152,153] |
| Lamotrigine | Plasma half-life 29 h | Oral, rectal | Substrate of P-glycoprotein |
[154] |
| Levetiracetam | High bioavailability, plasma half-life 6–8 h | Oral, intravascular, intramuscular, rectal | Substrate of P-glycoprotein |
[154,155,156] |
| Oxcarbazepine | Rapidly reduced to active metabolite 10,11-dihydro-10-hydroxy-carbamazepine, plasma half-life 1–3.7 h; plasma half-life of monohydroxy derivative ~9.3 h |
Oral | ~40% bound to plasma protein, CYP3A4 induction | [150,157] |
| Phenobarbital | Poor water solubility, plasma half-life 100 h | Oral, intravascular, rectal |
Substrate of P-glycoprotein, CYP450 inducer |
[154,158] |
| Phenytoin | Poor water solubility, plasma half-life 22 h | Oral, intravascular |
Highly bound to serum proteins, substrate of P-glycoprotein |
[154,159] |
| Valproate | Fatty acid derivative, plasma half-life 4–16 h | Oral, intravascular, rectal |
Highly bound to serum proteins | [159] |
| Zonisamide | Plasma half-life 50–69 h (plasma)/105 h (RBCs) | Oral | ~40% bound to plasma proteins | [160] |
| Stroke medications | ||||
| Atorvastatin (statin) |
Highly soluble, plasma half-life 7 h | Oral | Extensive first-pass metabolism, low oral bioavailability (14%), substrate of P-glycoprotein |
[161] |
| Apixaban (anticoagulant) |
Rapidly absorbed, plasma half-life 12 h | Oral | Substrate of P-glycoprotein and breastcancer resistance protein |
[162,163] |
| Aspirin (antiplatelet) |
Polar, small, plasma half-life of 15–20 min, platelet-inhibitory effect until platelet death (~10 days) | Oral, rectal, intravenous |
Highly bound to albumin (87% in vitro, ~93% in vivo) | [164,165] |
| Clopidogrel (antiplatelet) |
Inactive prodrug, 2-step bioactivation process (esterase hydrolysis with CYP2C19 and CYP3A4), plasma half-life 6 h |
Oral | Substrate of P-glycoprotein, low BBB permeability (50%), only ~15% is activated by CYP enzymes |
[166,167,168] |
| Dabigatran (anticoagulant) |
High polarity, low bioavailability (dabigatran not bioavailable but bioavailability of prodrug abigatranetexilate increases slightly to is 3–7%), plasma half-life 8 h | Oral | Prodrug is substrate of P-glycoprotein |
[166,169] |
| Hydrochlorothiazide (antihypertensive) |
Very poor water solubility, not metabolized, plasma half-life 6–12 h | Oral | Low absorption rate | [170,171] |
| Rivaroxaban (anticoagulant) |
CYP3A4/3A5 and CYP2J2 metabolism, high bioavailability (~80–100% with 10 mg dose), plasma half-life 5–9 h, | Oral | Substrate of P-glycoprotein and breast cancer resistance protein, high plasma protein binding ~92–95% |
[166,169,172] |
| Tissue plasminogen activator | Crosses BBB via LDL receptor-related protein-mediated transcytosis, inhibits P-glycoprotein, plasma half-life 4–5 min | Intravenous | Short window of administration (maximum 3–4.5 h), risk of brain hemorrhage |
[173,174,175] |
| Warfarin (anticoagulant) |
Rapid absorption, CYP2C9 metabolism, plasma half-life 20–60 h | Oral, intravenous | Substrate of P-glycoprotein |
[166,176,177] |
| Cancer drugs | ||||
| Carmustine | Lipophilic, rapidly crosses BBB, plasma half-life 15–30 min | Intravenous | Rapidly Metabolized |
[178] |
| Doxorubicin | Large size (greater than 0.4 kDa), plasma half-life 48 h | Intravenous | Too large for diffusion through phospholipid bilayer or intraendothelial cell junction pores, does not cross blood-brain barrier | [179,180] |
| Everolimus | Large size (MW ≈ 1000), CYP3A4, CYP3A5 and CYP2C8 metabolism, plasma half-life 28 h | Oral | Substrate of P-glycoprotein, variable oral bioavailability |
[181,182] |
| Lomustine | Lipophilic, rapidly crosses BBB, initial plasma half-life 6 h, second phase plasma half-life 1–2 days | Oral | Rapidly metabolized | [178,183] |
| Temozolomide | Small size, lipophilic, prodrug, plasma half-life 1.8 h | Intravenous | Resistance to temozolomide among 50% of patients with glioblastoma multiforme | [184,185] |
| TBI treatments | ||||
| Phenytoin | Free (unbound) drug can cross BBB, plasma half-life 22 h | Oral, Intravenous | 90% bound to serum albumin, 95% metabolized by liver, can cause dizziness in patients, careful dosing regimen must be followed due to metabolic enzyme saturation | [186,187,188] |
| Levetiracetam | Serum half-life 6–8 h | Oral, Intravenous | Substrate of P-glycoprotein | [186] |
| Hypertonic saline |
Contains a higher concentration of NaCl than the plasma and interstitial fluid | Intravenous | Caution must be taken with patients who have congestive heart failure or renal insufficiency | [189,190,191] |
| Mannitol | Contains a higher concentration of mannitol than the plasma and interstitial fluid | Intravenous | Unwanted blood-brain barrier damage can occur with high levels of hyperosmolar mannitol, eliminated quickly through renal excretion | [190,192,193] |
| Docosahexaenoic Acid (DHA) | Omega-3 polyunsaturated fatty acid, passive diffusion across BBB, plasma half-life 48 h for repeated administration | Oral | Partially metabolized by CYP enzymes | Phase 2 clinical trial (NCT03345550) completed in July 2021 [194,195] |
| Propranolol (beta-blocker) | Lipophilic, plasma half-life 3–6 h | Oral, intravenous | Mostly eliminated through renal excretion | [196,197,198] |
| Mesenchymal stem cells (only validated in animal models thus far) | Too large to cross BBB, release exosomes that can cross BBB | Intra-arterial, intravenous, intracerebral | Are not able to cross the BBB but act on brain inflammation from the periphery | [32,199] |