Pharmacokinetics of pioglitazone, a thiazolidinedione derivative, in male Naeini (Iranian fat-tailed) sheep

Figures & data

Figure 1.  Semilogaritmic plot of mean plasma concentration versus time after a single intravenous injection (•; n=4) and oral administration (o; n=4) of 10 mg/kg PGT in sheep.

Table 1. Pharmacokinetic parameters [mean±SEM (range); n=4] following a single oral or IV administration of PGT (10 mg/kg) in sheep.

Parameter	Oral^a	IV^b
C max (µg/mL)	10.2±1.3 (7.6–13.2)	–
A (µg/mL)	–	71.7±9.4
α (h^−1)	–	1.81±0.54
B (µg/mL)	–	42.0±12.9
β (h^−1)	–	0.22±0.07
t max (h)	6.4±0.3 (5.7–7.0)	–
t 1/2α (h)	–	0.49±0.13
t 1/2β (h)	4.42±0.21	4.04±0.88
k ab (h^−1)	0.16±0.01	–
k el (h^−1)	0.16±0.01	0.47±0.09
k 12 (h^−1)	–	0.68±0.15
k 21 (h^−1)	–	0.88±0.41
V ss (L/kg)	0.38±0.05	0.30±0.06
V 1 (L/kg)	–	0.16±0.04
V 2 (L/kg)	–	0.14±0.03
CL (Lh^−1 kg^−1)	0.06±0.01	0.08±0.02
AUC0 − ∞ (h µg/mL)	180.3±30.5	249±16
MRT (h)	–	4.7±1.0
AUMC (h^2 µg/mL)	–	1218±300
F (%)	62.4±6.9	–
^aAnalysed by non-compartmental approach.
^bAnalysed by two-compartment body model.
C max, maximum plasma concentration; A, zero time intercept of distribution slope in the two compartment model; B, zero time intercept of elimination slope in the two compartment model; α, distribution rate constant, β elimination rate constant, t max, time to maximum plasma concentration; t 1/2α, distribution half-life; t 1/2β, elimination half-life; k ab, rate of absorption constant; k el, rate of elimination constant; K 12, K 21, the distribution rate constants from central to peripheral compartment and back; V ss, volume of distribution at steady state; V 1 , the central volume of distribution; V 2 , the peripheral volume of distribution; CL, total body clearance; AUC, area under the plasma concentration–time curve; MRT, mean residence time; AUMC, area under the first moment–time curve.

Table 2. Comparison of several pharmacokinetic parameters for PGT in sheep, horse, rat and human following single oral dose administration of the drug.^a

		Sheep	Horse	Rat^b		Human^c
	Reference	This study	Wearn et al. (2010)	Umathe et al. (2008)	Fujita et al. (2003)	Eckland and Danhof (2000)		Budde et al. (2003)	Kalliokoski et al. (2008)
Parameter	Dose	10 mg/kg	1 mg/kg	10 mg/kg	10 mg/kg	7.5 mg	45 mg	45 mg	15 mg
C max (µg/mL)		10.2±1.3	0.5±0.4	13.00±1.50	13.6±1.9	–	1.5±0.5	1.3±0.7	0.6±0.1
t max (h)		6.4±0.3	1.9±1.4	1.63±0.75	2.8±1.1	1.5 (0.5–3.0)	3.0 (2.0–5.0)	2.0 (1.0–4.0)	1.8 (1.0–4.0)
		6.4 (5.7–7.0)
t 1/2 (h)		4.42±0.21	9.9±4.6	3.82 ±2.47	2.5±0.4	5.8 (3.5–9.0)^d	9.2±7.5	13.7±5.7	7.9±2.5
		4.5 (3.9–4.9)
k ab (h^−1)		0.16±0.01	–	–	0.38±0.08	(0.4–1.2)	–	–	–
		0.16 (0.14–0.18)
k el (h^−1)		0.16±0.01	–	0.22±0.08	0.26±0.04	–	–	–	–
CL (Lh^−1 kg^−1)		0.06±0.01	–	0.51±0.11^e	–	2.4 (1.72–4.17)^d,f	0.04±0.13	–	–
V d (L/kg)		0.38±0.05	–	2.40±0.73^e	0.27±0.03	0.25 (0.2–0.3)^d	–	–	–
^aAll data (except data for the present study; mean±SEM) are depicted as mean±SD and/or median (range).
^bData from female rats for Umathe et al. with mean body weight of 275 g; and male rat for Fujita et al.
^cAssuming a body weight of 70 kg, the dosage rates will be approximately 0.1, 0.6, 0.6 and 0.2 mg/kg.
^dData are related to IV administration of 5 mg PGT as mean (range).
^eThe origin values given in the literature for CL and V d are 0.14±0.03 L/h and 0.66±0.20 L, which are converted to Lh^−1 kg^−1 and L/kg, respectively.
^fValue of CL is mentioned as ‘L/h’ and will be equal to 0.034 Lh^−1 kg^−1, assuming an average weight of 70 kg for human.
C max, maximum plasma concentration; t max, time to maximum plasma concentration; t 1/2, half-life; k ab, rate of absorption constant; k el, rate of elimination constant; CL, total body clearance; V d volume of distribution; IV, intravenous.