Table 2.
Drug concentration and pharmacokinetic alterations in therapeutic hypothermia with their specific metabolism and elimination pathway
| Metabolic pathway | Temperature/subject population | Investigated Drug | concentration/PK parameters estimates |
|---|---|---|---|
| Flow/CYP2B/UGT | 34°C/healthy volunteers | Propofol [26] | Css↑ 28%, Inter-compartment CL↓ with temperature |
| Flow/CYP3A | 31.6°C/piglets | Fentayl [27] | Plasma conc↑25±11%, temperature and CYP3A4 dependency |
| Flow/bile/OATP | 32.5°C/male Wistar rats | ICG [28] | CL↓80%, MRT↑ 2-fold |
| Flow/bile/OATP | 32°C/rats | ICG [29] | Total CL↓ to 47%, AUC↑2-fold, CLb↓ |
| CYP3A | Moderate 32–34°C/TBI patients | Midazolam [35] | Plasma concentration ↑, Vd↑83%, CL↓, Ke↓ |
| CYP3A | 35.5–36.5°C/healthy volunteers | Midazolam [36] | CL↓ 11% per degree |
| CYP3A/PGP | <35, 35–35.9,36–36.9°C/volunteers | Vecuronium[37] | CL↓11.3% per degree |
| CYP3A | 32°C/In vitro microsome | Ethylmorphine [27] | Temperature dependent reaction, CYP3A4 activity ↓ to 69% |
| CYP2C9/CYP2C19 | 34 °C/brain damage patients | Phenytoin [30] | AUC↑180%, MRT↑180%, CL↓67% and Ke↓50% |
| CYP2C9/3A | 34.5°C/healthy volunteers | Neostigmine [39] | V1↓38%, no change in CL |
| CYP2C9/Renal | 32.5°C/male Wistar rats | S-acenocoumarol [28] | CL↓26% |
| CYP2C19/UGT | 30–31°C/TBI children | Phenobarbital [40] | Ke↓, renal metabolite excretion↓, Vd↑25% |
| CYP2D6/2B | Server <32°C/9 out of 11 children | Pentobarbital [41] | CL↓, Vd↓20%, no change in T1/2 |
| CYP2D6/2B | 30°C/perfused rat liver | Pentobarbital-2-c14 [42] | CLh↓50%, CLb↓ 71% |
| CYP2D6/Renal | 30.4°C/neurosurgical patients | Rocuronium [43] | CL↓ to 51%, MRT↑1.9 fold |
| CYP2E1 | 30°C/cardiac arrest rats | Chlorzoxazone [31] | Km↑116%, Clint↓44%,CL↓ 54%, Ke↓66% |
| UGT | 33–34°C/HIE infants | Morphine [46] | CL↓, potential toxic concentration in hypothermia |
| UGT | 30°C/dog | Morphine [47] | Conc in plasma and CSF↑, CL↓ 70%,T1/2β↑2-fold, MRT↑, Vd↓ |
| Transporter PGP | 32°C/in vitro kidney epithelial cell | Digoxin [48] | Direction from B to A ↓50% |
| PGP/OATP | 32°C/in vitro kidney epithelial cell | Quindine [48] | No change in 32°C |
| OATP/flow | 32.5°C/rats | ICG [28] | Bile excretion via OATP was extended |
| Renal filtration | 33.5°C/HIE infants | Gentamicin [50] | No change in CL, high concentration related to renal impairment |
| Renal filtration | 35°C/hypoxia newborn pig | Gentamicin [51] | No change in CL |
| Renal filtration/CYPs | 32°C/cats | Pancuronioum [53] | No change in CL, Vss↓ |
| Renal filtration/GFR | 32°C/rats | FD-4 [29] | No change in pharmacokinetics |
| Renal tubular secretion | 32°C/rats | PSP [29] | Total CL↓ 42%, plasma AUC↑2-fold, MRT↑, renal secretion ↓ |
Abbreviations: ICG: Indocyanine green; FD-4: Fluorescein isothiocyanate (FITC)-dextran; OATP: Organic anion transporter; CL: Systemic clearance; CLb: Bile clearance; Conc: Concentration; AUC: Area under curve; Ke: Elimination rate; Vd: Volume of distribution; V1: Volume of distribution in central compartment; Vss: Volume of distribution at steady state; MRT: Mean resident time; T1/2: Half- life; Km: Michaelis-Menten constant; Clint: Intrinsic clearance.