Table 2.

Disposition of unbound (R)- and (S)-methadone following chronic dosing of between 7.5 mg and 130 mg rac-methadone once daily in 18 patients enrolled in a maintenance programme.

Parameter1		Mean	Range	%C	P value2 (mean difference; 95% CI)
fu (%)	(R)-methadone	3.6	1.8–4.8	24	< 0.0001
	(S)-methadone	2.1	1.2–2.8	25	(1.5; 1.3, 1.8)
${\mathrm{C}}_{{\min \left(\mathrm{first}\right)}_u}^{\mathrm{ss}}$ (ng ml−1)	(R)-methadone	5.3	2.0–8.0	33	< 0.0001
	(S)-methadone	3.1	0.8–5.9	46	(2.2; 1.6, 2.8)
${\mathrm{C}}_{{\min \left(\mathrm{last}\right)}_u}^{\mathrm{ss}}$ (ng ml−1)	(R)-methadone	5.4	1.9–7.8	33	< 0.0001
	(S)-methadone	3.1	0.8–5.5	43	(2.3; 1.7, 2.9)
${\mathrm{C}}_{{\max }_u}^{\mathrm{ss}}$ (ng ml−1)	(R)-methadone	8.9	4.3–13.4	29	< 0.0001
	(S)-methadone	6.2	2.8–9.2	34	(2.7; 2.0, 3.5)
${\mathrm{C}}_{{\mathrm{av}}_u}^{\mathrm{ss}}$ (ng ml−1)	(R)-methadone	6.0	2.3–11.0	34	< 0.0001
	(S)-methadone	3.8	1.4–6.1	40	(2.3; 1.6, 2.9)
${\mathrm{AUC}}_{{\tau }_u}^{\mathrm{ss}}$ (ng ml−1 h)	(R)-methadone	117	28–268	51	0.0003
	(S)-methadone	70	16–126	46	(47; 26, 68)
CLu/F (ml min−1)	(R)-methadone	4611	2214–10590	46	0.0001
	(S)-methadone	7845	3994–17750	51	(−3235; −4590, −1879)
${\mathrm{CL}}_{R_u}$ (ml min−1)	(R)-methadone	847	256–1832	48	0.63
	(S)-methadone	819	265–1444	44	(28; −100, 155)
CLMD→EDDPu (ml min−1)	(R)-methadone	727	77–1890	70	0.0017
	(S)-methadone	1656	207–3506	66	(−930; −1406, −453)

¹f_u=unbound fraction; ${\mathrm{C}}_{{\min \left(\mathrm{first}\right)}_u}^{\mathrm{ss}}$=unbound plasma concentration, normalized to a 70 mg rac-methadone dose, predose; ${\mathrm{C}}_{{\min \left(\mathrm{last}\right)}_u}^{\mathrm{ss}}$=unbound plasma concentration, normalized to a 70 mg rac-methadone dose, 24 h after dosing; ${\mathrm{C}}_{{\max }_u}^{\mathrm{ss}}$=maximum measured unbound plasma concentration, normalized to a 70 mg rac-methadone dose; ${\mathrm{C}}_{{\mathrm{av}}_u}^{\mathrm{ss}}$=steady-state plasma concentration of unbound drug, normalized to a 70 mg rac-methadone dose; ${\mathrm{AUC}}_{{\tau }_u}^{\mathrm{ss}}$=area under the plasma unbound concentration–time curve during the interdosing interval; CL_u/F =apparent plasma clearance at steady-state of the unbound drug; ${\mathrm{CL}}_{R_u}$=renal clearance of the unbound drug; CL_MD→EDDPu=apparent partial intrinsic clearance of methadone to EDDP.

²Comparison of (R)-methadone vs (S)-methadone.