Pharmacokinetics of Intravenous and Oral Metformin and R,S-Verapamil in Sinclair, Hanford, Yucatan and Göttingen Minipigs

Figures & data

Figure 1. Mean (± SD, n = 4; n = 3 for Göttingen) metformin plasma concentration–time profiles.

Data shown following a 0.5 mg/kg intravenous dose (A) or 5 mg/kg oral dose (B) administration to fasted Yucatan (blue diamond), Hanford (red square), Sinclair (green triangle) or Göttingen (black circle) minipig.

Figure 2. Comparison of mean (± SD, n = 4; n = 3 for Göttingen) pharmacokinetics parameters.

Intravenous Clp (A) or oral AUC_0–48h(B) in various strains of minipig.

^aClp in Göttingen compared with other strains, p < 0.0001, Dunnett’s test.

Figure 3. Mean (+)-(R)-VER (square symbols) or (−)-(S)-VER (triangle symbols) plasma concentration (± SD, n = 4; n = 3 for Göttingen)–time profiles following a 0.2 mg/kg intravenous (open symbols) or 2 mg/kg oral (closed symbols) dose of R,S-VER to fasted Yucatan, Hanford, Sinclair or Göttingen minipig.

Figure 4. Comparison of mean (± SD, n = 4; n = 3 for Göttingen) pharmacokinetics parameters.

(A) Comparison of mean plasma clearance of (+)-(R)-VER and (−)-(S)-VER across four strains of minipig after intravenous administration of R,S-VER at 0.2 mg/kg. ^aSinclair compared with other strains, p < 0.05, Dunnett’s test, n = 4. (B) Comparison of mean AUC_0–48h ratio of (+)-(R)-NOR or (−)-(S)-NOR to their respective parent enantiomers after oral administration of R,S-VER at 2 mg/kg in various minipig strains.

Table 1. Age and weight-matched strains of minipig.

Strain	Age at first dose (months)	Body weight (kg)
Sinclair	4.5 ± 0.1	14.8 ± 2.1
Yucatan	4.2 ± 0.2	14.6 ± 0.3
Hanford	4.4 ± 0.0	14.3 ± 1.2
Göttingen	4.7 ± 0.3	11.3 ± 0.8

Table 2. A comparison of metformin clearance to glomerular filtration rate in humans and various minipig strains.

Species or minipig strain	GFR (ml/min//kg)	MET Clp (ml/min//kg)	Unbound Clp/GFR ratio^§
Human^†	1.8	6.4	3.6
Yucatan^‡	4.7	10.1	2.2
Hanford^‡	4.7	9.7	2.1
Sinclair^‡	4.7	8.7	1.9
Göttingen^‡	4.7	19.6	4.2

^†GFR data taken from [7]; MET Clp taken from [39].

^‡Data taken from [27], assuming similar GFR values across strains.

^§Calculated assuming unbound fraction of 1 for MET.

GFR: Glomerular filtration rate; MET: Metformin.

Table 3. Plasma protein binding of (+)-(R)-VER and (−)-(S)-VER in humans and various strains of minipig.

Plasma^† species, strain	Enantiomer	% Unbound (mean ± SD)^‡	% Bound (mean ± SD)^‡
Minipig Sinclair	(+)-(R)	17.5 ± 0.7	82.5 ± 0.7
	(-)-(S)	14.6 ± 0.4	85.4 ± 0.4
Minipig Yucatan	(+)-(R)	31.1 ± 1.4	68.9 ± 1.4
	(-)-(S)	29.1 ± 0.7	70.9 ± 0.7
Minipig Hanford	(+)-(R)	21.2 ± 0.8	78.8 ± 0.8
	(-)-(S)	19.7 ± 1.1	80.3 ± 1.1
Minipig Göttingen	(+)-(R)	28.6 ± 2.1	71.4 ± 2.1
	(-)-(S)	21.0 ± 0.8	79.0 ± 0.8
Human	(+)-(R)	12.6 ± 0.3	87.4 ± 0.3
	(-)-(S)	19.1 ± 0.5	80.9 ± 0.5

^†1 μM test concentration.

^‡n = 6 replicates for all species.

Table 4. General direction of enantioselectivity for exposure, clearance and protein binding in various species.

Parameter	^†Rat	^†Human	Minipig
Oral AUC	(-)-(S) > (+)-(R)	(+)-(R) > (-)-(S)	(+)-(R) = (-)-(S)
Clp	(+)-(R) > (-)-(S)	(-)-(S) > (+)-(R)	(+)-(R) = (-)-(S)
Plasma binding	(+)-(R) > (-)-(S)	(-)-(S) > (+)-(R)	(+)-(R) > (-)-(S)

^†Data taken from [20,27].

(−)-(S)-VER is metabolized more actively than the R-form in human resulting in a 2.5-fold higher concentration of the (+)-(R)-VER enantiomer in plasma.

AUC: Area under the curve.

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