Human Biliary Amount Prediction Using Simple, Bile Flow-Rate Corrected and Uridine Diphosphate Glucuronosyltransferase Activity Corrected Allometric Methods

Figures & data

Table 1. Physiological parameters used in the allometry scaling.

Species	Body weight (kg)	Bile flow^† (ml/min)	UDPGT activity^‡ (nmol/min/mg protein)
Mouse	0.025	0.0014	1.012
Rat	0.25	0.0156	3.059
Monkey	5	0.0868	7.429
Dog	12	0.0833	5.499
Human	70	0.243	3.163

^†Data taken from [12].

^‡Data taken from [5].

UDPGT: Uridine diphosphate glucuronosyltransferase.

Table 2. Listing of species, doses, route, labeling, collection period and percent recovery in bile of various compounds/drugs that were subjected to interspecies scaling for allometry prediction.

Compounds/drugs	Species	Dose (mg/kg), route	Labeling	Collection period	% Recovery in bile	Ref.
Atorvastatin	Rat	10 mg/kg, p.o.	^14C	0–48	69.7^†	[13]
	Dog	10 mg/kg, p.o.	^14C	0–48	34.0^†	[13]
Brivanib alaninate	Rat	100 mg/kg, p.o.	^14C	0–48	78.4	[16]
	Monkey	10 mg/kg, p.o.	^14C	0–72	47.7	[16]
Bromocriptine	Rat	3 mg/kg, p.o.	^14C	0–48	31.3	[19]
	Monkey	0.025 mg/kg, p.o.	^14C	0–8	32.0	[19]
Carvedilol	Rat	10 mg/kg, p.o.	^14C	0–48	53.6	[22]
	Dog	30 mg/kg, p.o.	^14C	0–48	47.8	[22]
Cefpiramide	Rat	iv.	^NA	^NA	58.0	[11]
	Dog	iv.	^NA	0–9	19.0	[11]
Cefotetan	Rat	iv.	^NA	^NA	48.0	[11]
	Dog	iv.	^NA	0–24	17.0	[11]
Ceftriaxone	Rat	iv.	^NA	^NA	62.0	[11]
	Dog	iv.	^NA	^NA	63.0	[11]
Digoxin	Rat	iv.	^NA	^NA	31.0	[11]
	Dog	iv.	NA	^NA	7.0	[11]
Doxorubicin	Rat	iv.	NA	NA	17.0	[11]
	Dog	iv.	NA	NA	10.0	[11]
Erythromycin	Rat	iv.	NA	NA	30.0	[11]
	Dog	iv.	NA	NA	5.0	[11]
Linagliptin	Mouse	^b	^14C	0–6	46.0	[15]
	Rat	^b	^14C	0–6	41.0	[15]
	Monkey	^b	^14C	0–6	27.0	[15]
Muraglitazar	Rat	10 mg/kg, p.o.	^14C	0–24	65.1	[14]
	Dog	40 mg/kg, p.o.	^14C	0–24	66.0	[14]
	Monkey	5 mg/kg, p.o.	^14C	0–48	36.0	[14]
Napsagatran	Rat	iv.	^14C	^NA	61.0	[11]
	Dog	iv.	^14C	^NA	97.0	[11]
Odanacatib	Rat	1 mg/kg, iv.	^14C	0–72	63.0	[17]
	Dog	1 mg/kg, iv.	^14C	0–72	16.0	[17]
	Monkey	1 mg/kg, iv.	^14C	0–72	71.0	[17]

^†Percent recovery of parent.

iv.: Intravenous; NA: Data not available; p.o.: Per oral.

Figure 1. Illustration of interspecies scaling of percent bile recovery.

Using the simple allometry (A, D & G), bile flow-rate corrected (B, E & H) and UDPGT corrected (C, F & I) methods of linagliptine, muraglitazar and odanacatib, respectively.

UDPGT: Uridine diphosphate glucuronosyltransferase.

Table 3. Fold difference in the predicted and observed percent recovery of drug/drug-related amount of various compounds/drugs using different allometry methods.

Compound name	Human (literature value)	Ref.	Scaled % amount in bile
			Simple allometry		Bile flow correction		UDPGT activity correction
			Predicted	Fold difference	Predicted	Fold difference	Predicted	Fold difference
Atorvastatin	90.0^†	[23]	24.5	0.3	18.0	0.2	55.6	0.6
Brivanib alaninate	81.5^‡	[16]	30.8	0.4	49.8	0.6	157.9	1.9
Bromocriptine	82.3^‡	[19]	32.6	0.4	52.9	0.6	167.5	2.0
Carvedilol	60.0^‡	[20]	45.4	0.8	33.4	0.6	103.0	1.7
Cefpiramide	28.0^§	[11]	11.4	0.4	8.4	0.3	26.0	0.9
Cefotetan	11.0^¶	[11]	10.7	1.0	7.8	0.7	24.1	2.2
Ceftriaxone	30.0^¶	[11]	63.5	2.1	46.7	1.6	144.1	4.8
Digoxin	41.0^¶	[11]	3.6	0.1	2.6	0.1	8.1	0.2
Doxorubicin	14.0^§	[11]	7.9	0.6	5.8	0.4	17.8	1.3
Erythromycin	13.0^¶	[11]	2.2	0.2	1.6	0.1	5.0	0.4
Linagliptin	58.2^‡	[21]	21.3	0.4	69.2	1.2	143.2	2.5
Muraglitazar	39.9^#	[14]	45.7	1.1	43.6	1.1	135.8	3.4
Napsagatran	60.0^#	[11]	119.8	2.0	88.1	1.5	272.1	4.5
Odanacatib	74.5^‡	[18]	17.8	0.2	17.0	0.2	52.9	0.7

^†Atorvastatin is primarily eliminated via hepatic biliary excretion, with less than 2% recovery in the urine based on this 90% was assumed as excreted in bile.

^‡Percent recovery in feces.

^§T-tube method for bile collection.

^¶Duodenal perfusion method for bile collection.

^#Bile collection method information was not available.

UDPGT: Uridine diphosphate glucuronosyltransferase.

Figure 2. Illustrative plot comparing the goodness of bile recovery prediction using fold-difference criteria of various drugs.

Using (A) simple allometry, (B) bile flow-rate corrected allometry and (C) UDPGT activity corrected allometry (inset: an expanded scale is provided for easy visualization of the fold differences for the three allometry methods).

UDPGT: Uridine diphosphate glucuronosyltransferase.

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