Table I.
Summary of the Rat Brain Distribution Data for Model Development and External Validation
| Study design | Model development | External validation | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Published data | Newly produced data | Published data | Newly produced data | ||||||||||
| Acetaminophen | Atenolol | Methotrexate | Morphine | Morphine | Quinidine | Remoxipride | Paliperidone | Phenytoin | Risperidone | Acetaminophen | Remoxipride | ||
| Species | rat | rat | rat | rat | rat | rat | rat | rat | rat | rat | rat | rat | |
| Nr of animals | 16 | 5 | 23 | 65 | 18 | 41 | 29 | 21 | 14 | 16 | 8 | 65 | |
| Dosage, mg/kg (infusion time, min) | 16 (10) | 10 (1) | 40, 80 (10) | 4, 10, 40 (10) | 10, 40 (10) | 10, 20 (10) | 4, 8, 16 (30) | 0.5 (20) | 20, 30, 40 (10) | 2 (20) | 200a (1) | 0.7, 5.2, 14 (10) | |
| Nr of samples (sampling times, min) | plasma | 67 (0–240) | 32 (0–120) | 186 (0–300) | 825 (0–360) | 306 (0–190) | 313 (0–360) | 189 (0–240) | 182 (0–360) | 109 (0–480) | 124 (0–360) | 67 (0–180) | 290 (0–240) |
| dialysate | 592 (0–240) | 106 (0–120) | 1065 (0–300) | 238 (0–360) | 299 (0–180) | 1678 (0–360) | 125 (0–240) | 660 (0–240) | 152 (0–480) | 436 (0–240) | 72 (0–180) | 489 (0–240) | |
| Active transport inhibitor | – | – | probenecidb | GF120918c | – | tariquidarc | – | tariquidarc | tariquidarc, probenecidb | tariquidarc | – | – | |
| Dosage of active transport inhibitor, mg/kg (infusion time, min) | – | – | 150 (10) | 6 (cont)d | – | 15 (10) | – | 15 (10) | 15 (10) 150 (10) | 15 (10) | – | – | |
| Data | |||||||||||||
| plasma | X | X | X | X | X | X | X | X | X | X | X | X | |
| brainECF | X | X | X | X | X | X | X | X | X | X | X | X | |
| CSFLV | X | X | X | X | |||||||||
| CSFCM | X | X | X | X | X | X | |||||||
| References | (6) | (69) | (25) | (70) | (71) | (24) | (26) | (72) | |||||
brain ECF a brain extracellular fluid compartment, CSF LV a compartment of cerebrospinal fluid in lateral ventricle, CSF CM a compartment of cerebrospinal fluid in cisterna magna
a; mg, b; inhibitor of MRPs, OATs and OATPs, c; inhibitor of P-gp,d; continuous infusion