Pharmacokinetic drug interactions in liver disease: An update

Table 1 Differential inhibitory effects of fluvoxamine on systemic lidocaine and theophylline clearances, and on partial metabolic clearances of theophylline in healthy subjects and cirrhotic patients

Parameter	Healthy subjects		Patients with cirrhosis
			Child A		Child C
	Placebo	Fluvoxamine	Placebo	Fluvoxamine	Placebo	Fluvoxamine
CL lidocaine	12.10 ± 3.38	4.85 ± 4.85c	9.83 ± 3.99	5.06 ± 1.75c	4.21 ± 1.56e	3.65 ± 0.99
Inhibition (%)	60 (53-77)		44 (28-59)		9 (0-19)e
Fluvoxamine AUC0-14		866 ± 331		1277 ± 381		2316 ± 790d
CL theophylline	0.825 ± 0.201	0.302 ± 0.080c	0.660 ± 0.231	0.310 ± 0.104a	0.296 ± 0.124d	0.251 ± 0.151
Inhibition (%)	64 (59-69)		55 (46-66)		14 (0-29)
CLf 3-MX	0.192 ± 0.069	0.008 ± 0.007c	0.124 ± 0.051	0.011 ± 0.017c	0.037 ± 0.012d	0.023 ± 0.013a
Inhibition (%)	97 (93-100)		92 (84-100)		38 (18-58)
CLf 1-MU	0.220 ± 0.089	0.021 ± 0.019c	0.178 ± 0.072	0.026 ± 0.018c	0.066 ± 0.025d	0.039 ± 0.019a
Inhibition (%)	93 (89-98)		83 (73-93)		36 (15-57)
CLf 1,3-DMU	0.290 ± 0.070	0.136 ± 0.024c	0.222 ± 0.058	0.138 ± 0.026c	0.087 ± 0.040d	0.079 ± 0.037
Inhibition (%)	58 (49-67)		43 (29-58)		7 (0-22)
CLR theophylline	0.123 ± 0.033	0.136 ± 0.030	0.136 ± 0.050	0.135 ± 0.043	0.106 ± 0.047	0.110 ± 0.062
Inhibition (%)	-		-		-
Fluvoxamine Css		75 ± 26		95 ± 40		130 ± 26b

Data are taken or calculated from Orlando et al[29] 2004 and Orlando et al[30] 2006; all clearance values are expressed as mL/min per kg; inhibition values are given as means with 95% confidence limits.

^aP < 0.01,

^cP < 0.001 vs placebo;

^eP < 0.001 vs healthy subjects;

^bP < 0.01,

^dP < 0.001 vs healthy subjects and Child’s grade A patients. CL: Systemic clearance; CL_f: Formation clearance; 3-MX: 3-methylxanthine; 1-MU: 1-methyluric acid; 1,3-DMU: 1,3-dimethyluric acid; CL_R: Renal clearance; AUC_0-14: Area under plasma-concentration-time curve from 0 h to 14 h at steady state (ng/h/mL); C_ss: Steady-state trough concentration (ng/mL).

Table 2 Effect of erythromycin on the pharmacokinetic parameters of quinine and 3-hydroxyquinine in healthy subjects and cirrhotic patients

Parameter	Healthy subjects		Patients with cirrhosis
			Child A		Child C
	Placebo	Erythromycin	Placebo	Erythromycin	Placebo	Erythromycin
CL quinine	1.775 ± 0.310	1.161 ± 0.309a	1.504 ± 0.362	1.040 ± 0.303a	1.281 ± 0.394b	1.401 ± 0.534
Inhibition (%)	33 (27-38)		30 (26-34)		-7 (-16-2)f
CLf 3-hydroxiquinine	0.174 ± 0.051	0.059 ± 0.017c	0.140 ± 0.077	0.056 ± 0.032c	0.085 ± 0.028d	0.037 ± 0.023c
Inhibition (%)	65 (61-70)		61 (56-67)		59 (46-72)
Unbound quinine (%)	6.7 ± 0.8	9.4 ± 1.0c	7.1 ± 1.6	10.3 ± 2.8c	11.9 ± 3.7f	19.9 ± 5.5cf
Increase (%)	41 (28-55)		45 (33-55)		76 (42-111)b
CLu quinine	26.81 ± 11.49	12.30 ± 3.16c	21.18 ± 8.45	10.10 ± 3.88c	10.95 ± 2.19f	7.24 ± 2.77bc
Inhibition (%)	51 (44-59)		50 (45-55)		35 (21-48)b
CLuf 3-hydroxiquinine	2.63 ± 0.88	0.64 ± 0.20c	1.97 ± 1.09	0.55 ± 0.31c	7.01 ± 3.33f	4.06 ± 2.58ad
Inhibition (%)	75 (70-80)		73 (70-77)		74 (64-84)
Erythromycin Css		1.33 ± 0.25		1.18 ± 0.44		1.85 ± 1.00

Data are taken or calculated from Orlando et al[47]; all clearance values are expressed as mL/min per kg; inhibition or increase values are given as means with 95% confidence limits.

^aP < 0.01,

^cP < 0.001 vs placebo;

^bP < 0.05 vs healthy subjects and patients with Child grade A cirrhosis;

^dP < 0.001 vs healthy subjects and P < 0.05 vs patients with Child grade A cirrhosis;

^fP < 0.001 vs healthy subjects and patients with Child grade A cirrhosis. CL: Systemic clearance; CL_f: Formation clearance; CL_u: Unbound systemic clearance; CL_uf: Unbound formation clearance; C_ss: Steady-state trough concentration (μg/mL).