. 2018 Jul;70(3):621–660. doi: 10.1124/pr.117.015198

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 (2012a), Unpublished data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 (2012a), Unpublished data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 (2015b), Unpublished data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.