TABLE 2

Pharmacokinetic comparison for (2R,6R) and (2S,6S)-HNK in humans and rodents

Values represent mean ± S.D.

Species	Drug	Administration Paradigm	Tissue	C_max (R,S)-KET (plasma: µM; brain: µmol/kg)	C_max (R,S)-KET (plasma: ng/ml; brain: ng/g)	AUC_last (R,S)-KET (plasma: h.µM; brain h. µmol/kg)	AUC_last (R,S)-KET (plasma: h.ng/ml; brain: h.ng/g)	C_max (2R,6R;2S,6S)-HNK (plasma: µM; brain: µmol/kg)	C_max (2R,6R;2S,6S)-HNK (plasma: ng/ml; brain: ng/g)	AUC_last (2R,6R;2S,6S)-HNK (plasma: h.µM; brain h. µmol/kg)	AUC_last (2R,6R;2S,6S)-HNK (plasma: h.ng/ml; brain: h.ng/g)	References
Humans	(R,S)-KET	0.5 mg/kg, 40-min i.v. infusion	Plasma	0.75 ± 0.23 (BD)	177.23 ± 53.8 (BD)	4.10 (BD)	975.4 (BD)	0.16 ± 0.06 (BD)	37.59 ± 14.23 (BD)	5.70 (BD)	1366 (BD)	Zarate et al. (2012a), Unpublished data
Humans	(R,S)-KET	0.5 mg/kg, 40-min i.v. infusion	Plasma	0.86 ± 0.43 (MDD)	204.13 ± 101.46 (MDD)	3.67 (MDD)	873.5 (MDD)	0.097 ± 0.05 (MDD)	23.19 ± 11.88 (MDD)	4.33 (MDD)	1038 (MDD)	Zarate et al. (2012a), Unpublished data
Rats	(R,S)-KET	40 mg/kg, i.v. infusion	Plasma	34.52 ± 2.93	8206 ± 697	48.01 ± 21.30	11,410 ± 5064	18.59 ± 2.81	4455 ± 673	141.19 ± 18.5	33,843 ± 4432	Moaddel et al. (2015b), Unpublished data
	(R,S)-KET	40 mg/kg, i.p. infusion	Brain	137 ± 6	32,600 ± 1400	N/A	N/A	30 ± 5	7200 ± 1200	N/A	N/A	Paul et al. (2014)
	(R)-KET	20 mg/kg, i.v. infusion	Plasma	14.4 ± 1.68^{^a}	3430 ± 400^{^a}	N/A	N/A	1.44 ± 0.48^{^b}	345 ± 115^{^b}	N/A	N/A	Moaddel et al. (2015b)
	(R)-KET	20 mg/kg, i.v. infusion	Brain	68.84 ± 8.12^{^a}	16,365 ± 1931^{^a}	N/A	N/A	1.14 ± 0.20^{^b}	274 ± 47^{^b}	N/A	N/A
	(S)-KET	20 mg/kg, i.v. infusion	Plasma	11.49 ± 2.25^{^c}	2732 ± 535^{^c}	N/A	N/A	5.52 ± 0.28^{^d}	1323 ± 67^{^d}	N/A	N/A
	(S)-KET	20 mg/kg, i.v. infusion	Brain	65.25 ± 1.91^{^c}	15,512 ± 453^{^c}	N/A	N/A	3.21 ± 0.55^{^d}	769 ± 133^{^d}	N/A	N/A
	(R,S)-norKET	20 mg/kg, i.v. infusion	Brain	N/A	N/A	N/A	N/A	16 ± 3^{^b}	N/A	N/A	N/A	Paul et al. (2014)
	(2S,6S)-HNK	20 mg/kg, i.v. infusion	Brain	N/A	N/A	N/A	N/A	127 ± 4^{^d}	N/A	N/A	N/A	Paul et al. (2014)
		20 mg/kg, i.v. infusion	Plasma	N/A	N/A	N/A	N/A	49.89 ± 1.52^{^d}	11,958 ± 364^{^d}	120.91 ± 25.71^{^d}	28,981 ± 6162^{^d}	Moaddel et al. (2015b)
		20 mg/kg, i.v. infusion	Brain	N/A	N/A	N/A	N/A	127.09 ± 3.51^{^d}	30,463 ± 841^{^d}	N/A	N/A
		20 mg/kg, oral gavage	Plasma	N/A	N/A	N/A	N/A	19.66 ± 5.05	4713 ± 1211	42.22 ± 5.48	10,120 ± 1313
		20 mg/kg, oral gavage	Brain	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Mice	(R,S)-KET	10 mg/kg, i.p. injection	Plasma	2.36 ± 0.36	561.89 ± 86.09	0.75	177.9	2.81 ± 1.16	674.59 ± 278.23	2.01	480.9	Zanos et al. (2016)
	(R,S)-KET	10 mg/kg, i.p. injection	Brain	4.89 ± 0.85	1162.34 ± 202.05	2.07	492.2	2.08 ± 0.21	498.35 ± 50.99	2.49	597.0	Zanos et al. (2016)
	(R)-KET	10 mg/kg, i.p. injection	Plasma	1.40 ± 0.18^{^a}	332.8 ± 42.99^{^a}	0.44^{^a}	104.8^{^a}	2.83 ± 0.31^{^b}	678.3 ± 74.54^{^b}	1.85^{^b}	443.0^{^b}	Unpublished data
	(R)-KET	10 mg/kg, i.p. injection	Brain	7.93 ± 1.93^{^a}	1886 ± 459.6^{^a}	2.48^{^a}	591.9^{^a}	2.47 ± 0.31^{^b}	590.9 ± 74.10^{^b}	2.58^{^b}	618.7^{^b}	Zanos et al. (2016)
	(S)-KET	10 mg/kg, i.p. injection	Plasma	4.32 ± 1.12	1028 ± 266.7^{^c}	1.23^{^c}	293.1^{^c}	2.97 ± 0.87^{^d}	711.5 ± 209.4^{^d}	3.62^{^d}	868.1^{^d}	Unpublished data
	(S)-KET	10 mg/kg, i.p. injection	Brain	7.33 ± 2.36^{^c}	1743 ± 560.6^{^c}	2.03^{^c}	483.1^{^c}	2.21 ± 0.46^{^d}	530.7 ± 111.2^{^d}	4.15^{^d}	995.8^{^d}	Zanos et al. (2016)
	(2S,6S)-HNK	10 mg/kg, i.p. injection	Plasma	N/A	N/A	N/A	N/A	17.57 ± 8.72^{^d}	4211 ± 2089^{^d}	10.16^{^d}	2435^{^d}	Unpublished data
	(2S,6S)-HNK	10 mg/kg, i.p. injection	Brain	N/A	N/A	N/A	N/A	15.70 ± 8.98^{^d}	3764 ± 2152^{^d}	6.55^{^d}	1570^{^d}	Zanos et al. (2016)
	(2R,6R)-HNK	10 mg/kg, i.p. injection	Plasma	N/A	N/A	N/A	N/A	10.79 ± 4.76^{^b}	2587 ± 1141^{^b}	2.43^{^b}	583.5^{^b}	Unpublished data
	(2R,6R)-HNK	10 mg/kg, i.p. injection	Brain	N/A	N/A	N/A	N/A	10.66 ± 5.85^{^b}	2556 ± 1402^{^b}	2.19^{^b}	525.3^{^b}	Zanos et al. (2016)

BD, bipolar disorder; MDD, major depressive disorder.
↵^a Reported values represent (R)-KET levels.
↵^b Reported values represent (2R,6R)-HNK levels.
↵^c Reported values represent (S)-KET levels.
↵^d Reported values represent (2S,6S)-HNK levels.