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EC number: 247-156-8
CAS number: 25640-78-2
4-Isopropylbiphenyl, 4-MIPB, [CAS No. 7116-95-2] is a representative position isomer of the target compound, MIPB isomer mixture [CAS No.25640-78-2] accounting for about 45% of MIPB. Thus it may serve as model and marker substance for the ADME complex. Metabolism was determined to proceed in two steps. First, the isopropyl side chain is hydroxylated at C1 or C2 to the corresponding alcohol followed in part by further oxidation to carboxylic acid. In a second step, the biphenyl ring system can be hydroxylated with resulting products being conjugated for excretion.
Toxicokinetic and metabolism studies
were performed using either a single isomer (mostly 4-, para isomer) of
(isopropylbiphenyl, MIPB) or a mixture of 3- and 4-isopropylbiphenyl as
present in the technical product. Results are generally the same not
requiring separate consideration of different isomers. Information from
one isomer applies to the total substance.
4-Isopropylbiphenyl is easily absorbed
from the gastrointestinal tract as demonstrated after oral
administration to rats. Uptake is quantitative and parent compound and
metabolites are present in blood already after 0.5 hours with peak
levels at about 4 hours (Sullivan 1978).
48 hours after oral administration of
radiolabelled 4-isopropylbiphenyl, radioactive was found mostly in liver
(5.25 µg equiv./g), fat (4.73 µg equiv./g), and kidney (0.94 µg
equiv./g). In other tissues, lower amounts were found (from 0.63 to 0.05
µg equiv./g) - tissues in decreasing order: blood, lung, heart, spleen,
muscle, and brain). Isopropylbiphenyl and/or metabolites seem to be
sequestered in fatty tissue and then released at slower rates into the
blood stream for ultimate metabolism and excretion (Sullivan 1978.
Two major steps were identified in the
metabolic pathway of isopropylbiphenyl. In a first step,
biotransformation takes place at the isopropyl side chain (oxidation to
alcohols and subsequently also to carboxylic acid). In a second step,
the aromatic biphenyl ring system is hydroxylated, probably at the 4'
position. These hydroxybiphenyl derivatives can be conjugated and
Metabolic transformations at the
isopropyl side chain occur via two pathways. In one pathway, the primary
carbon of the isopropyl side chain (C1) is oxidised. The resulting
alcohol I could not be isolated in vivo. It is considered an
intermediate in formation of the carboxylic acid II which was identified
in blood. The second pathway is characterised by oxidation of the
tertiary carbon atom (C2) of the isopropyl side chain. The resulting
tertiary alcohol III was found in blood. The corresponding carboxylic
acid as subsequent oxidation product could not be identified and does
not seem to be generated.
In the blood of rats the following
metabolites of 4-isopropylbiphenyl were found.
- 2-(biphenyl-4-yl)propionic acid
(II), (major metabolite) (following also named propionic acid)
(resulting from pathway 1).
- 2 (biphenyl-4-yl)propan-2-ol (III)
(minor metabolite) (following also named propan-2-ol) (resulting from
acid (major metabolite) (IV) (following also named hydroxypropionic acid
(product of combined pathway 1 and 2)
In urine and bile of rats, except one
very minor metabolite, only ring hydroxylated products were identified.
acid (V) (major metabolite) (derivative of propionic acid)
(VI) major metabolite (derivative of propan-2-ol)
(VII) (very minor metabolite (derivative of primary oxidation product
(alcohol) at C1 of isopropyl side chain)
acid (VIII) (very minor metabolite) (derivative of hydroxpropionic acid)
- 4'OH-4-isopropylbipheny (IX) (very
minor metabolite) (ring hydroxylated parent compound)
(X) (very minor metabolite (dialcohol at C1 and C2 of isopropyl side
chain, not identified in blood)
It is noteworthy that one of the major
metabolites in blood (hydroxpropionic acid IV), is found in urine/bile
only in a very minor amount. In rats, this metabolite is not or only
minutely excreted neither as itself nor as ring hydroxylated product. In
further studies, it was found that this metabolite is sequestered in the
kidney of rats forming calculi and causing severe nephrotoxicity.
General principles of metabolism
(primary and secondary step, pathway 1 and pathway 2) are the same in
other species than rats. But preferences in metabolic pathways and
number and amount of metabolites formed may be different. In addition to
rats, metabolism was studied in dogs, monkeys and man. In the following
table, the metabolites identified for the four species are compiled.
They are differentiated in circulating (blood) and excreted
(urine/bile). In rats, excreted metabolites were conjugated. For other
species, this information is not reported.
propionic acid (II) (+)
propionic acid (II)
hydroxy-propionic acid (IV) (+)
hydroxy-propionic acid (IV)
propan-2-ol (III) (+-)
(OH-)propionic acid (V) (+)
(OH-)propan-2-ol (VI) (+)
(OH-)propanol (VII) (--)
(OH-)hydroxy-propionic acid (VIII) (--)
(OH-)hydroxy- propanol (X) (--)
(OH-)propionic acid (V)
Explanation to the table above:
With (OH-) the phenolic
hydroxy-substituent at the biphenyl ring system is characterised while
hydroxy- denotes the alcoholic OH group at C2 of the three carbon side
chain. The biphenyl ring system is also attached to this carbon atom.
(+) indicates a major metabolite in the respective compartment, (-) a
minor one. If abundance is not indicated, the order is decreasing within
Rat is the only species among the
tested species that is not able to excrete metabolites but only after
ring hydroxylation and conjugation. In other species, some of the
metabolites can be excreted without further ring hydroxylation.
Intermediate metabolites are indicated by excretion of metabolites not
present in blood.
Hydroxy-propionic acid IV is only
formed in rats and dogs. In dogs it can be excreted unchanged not
leading to accumulation. In monkey and man it could not be detected even
if both pathways (oxidation at C1 and C2) are utilised.
Observation of renal toxicity in rats
caused by sequestration of hydroxy-propionic acid in kidney is
restricted to this species as in the other species investigated, this
metabolite is directly excreted (dog) or not generated at all (monkey,
After oral or intraperitoneal
administration of radiolabelled isopropylbiphenyl, ca. 85 % of
radioactivity was excreted into urine and bile/faeces within 48 h. After
oral administration, excretion in urine was ca. 40%, in bile/faeces ca.
45-48%. No radioactivity was found in air expired by rats within 48 h
Special considerations related to
renal toxicity in rats
There is experimental evidence that
high doses of the 4-isopropyl isomer are nephrotoxic in rats, related to
accumulation of a particular metabolite predominantly formed in this
species (see above and endpoint study records in IUCLID Sect. 7.1.1
"Toxicokinetics": Sullivan et al. 1977/1978). Based on pharmacokinetic
investigations into the species-specific metabolism as well as chronic
toxicity studies in monkey and dog, 4-IPB failed to induce the
development of nephrotoxicity in monkey and dog (short communication in
Sullivan et al. 1977, p. 39). Further investigations into the
human-specific metabolism of 4-IPB demonstrated a similarity to that of
the dog. The synopsis of all results, metabolic/toxicokinetic as well as
toxicological, resulted in the conclusion that 4-IPB would not
demonstrate nephrotoxicity in humans (see Sullivan et al. 1977, p.
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