Current Medical Research and Opinion
`
`Vol. 4, No. 10, 1977
`
`Human studies on the
`bioavailability of a
`quaternary ammonium compound,
`tiemonium iodide and
`tiemonium methosulphate
`
`I. T. Scoular,$ B.Sc., PbD.,
`Anne Monks, B.Sc.,
`C.Burgess, M.B.,Ch.B., M.R.C.P.,
`and
`P. Turner, M.D., B.Sc.,F.R.C.P.
`
`Department of Clinical
`Pharmacology, St. Batholomew’s
`Hospital, London, England
`Received: 2nd May 1977
`
`Curr. Med. Res. Opin., (1977), 4, 732.
`Summary
`Five volunteers were administered capsules containing 14C-labelled tienionium iodide
`and 4 volunteers received capsules of 14C-labelled tiemonium methosulphate. Serum,
`urine and faecal levels of tiemonium were measured. The percentage of the dose
`absorbed was determined after a further labelled intravenous injection into 3 of the
`volunteers. The drug appeared to be poorly absorbed, as expected for quaternary
`ammonium compounds, but there was no diference in the bioavailability of’ these two
`tiemonium salts.
`
`Key words: Tiemonium - quaternary ammonium compounds - radioisotope scanning
`- hiopharmaceutics - pharmacokinetics
`
`Introduction
`Previous work on the pharmacokinetics of quaternary ammonium compounds in
`animals and man has been limited by the lack of serum level data. Early work was
`carried out on benzomethamine,5 atropine, and I-hyoscyamine. More recently,
`hyoscine butylbromide (butylscopolamine) has been st~died.2-~.7<9 All these
`
`Figure 1. Structural formula of tiernonium
`
`*indicates position of 4C
`‘;Present address: Pharmaceutical Division, Reckitt and Colman Ltd., Dansom Lane,
`Hull HU8 7DS, England
`
`732
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`1. T. Scoular, Anne Monks, C. Burgess and P. Turner
`
`compounds were found to be poorly absorbed, hence recovery in the urine was low.
`the majority of the dose being eliminated directly in the faeces.
`In an investigation on the bioavailability of two salts of tiemonium (‘Viscer-
`algine’t), the iodide and methosulphate, the use of radioactively labelled compounds
`has made it possible to follow the time-course of the drug in the plasma of volunteers
`for up to 8 hours and, therefore, to correlate serum levels of a quaternary ammonium
`compound with its absorption and excretion pattern in man.
`Chemically, tiemonium is 4-[3-hydroxy-3-phenyl-3-(2-thienyl)-propyl-4-methyl-
`morpholinium. Tts structural formula is shown in Figure 1.
`
`Methods and materials
`The oral dose of tiemonium used in the trial was decided after an initial tolerance
`study in 2 healthy male volunteers. Nine healthy malevolunteers, aged 30 to 58 years,
`then took 3 unlabelled 50 mg capsules of either salt ina blind fashionat 09.00,13.00,
`and 18.00 hours on the day preceding the trial. A fourth 4C-labelled capsule (30pCi)
`was administered at 08.30 hours on the day of the trial, the subject havingfastedfor
`12 hours before this dose. A fifth non-labelledcapsule was administered at 13.00 hours
`on the day of the trial, after a light lunch. Fluids were permitted up to 1 hour before
`oral administration of the product at 08.30 hours. Blood samples were taken at 0.5,
`I , 1.5,2,4,6,8,24,48 and 72 hours after administration of the radioactive dose, and
`were then centrifuged to obtain serum. Urine and faecal samples were collected at
`24-hour intervals, up to 72 hours. Following a similar regimen, 3 further volunteers
`received an injection of 5 mg tiemonium (5pCi) which replaced the fourth oral
`capsule. Blood sampling in these volunteers was at 0.1,0.2,0.3,0.75, I , 1.5, 2, 3,4,
`7 and 11 hours.
`Radioactivity in the biological samples was measured by liquid scintillation
`counting in a Packard Tri-Carb Spectrometer Model 2425. Correction for quenching
`was made by the use of an automatic external standard. Serum (1 ml) was pipetted
`into a counting vial containing 10 ml Instagel. Urine was treated similarly. Faecal
`samples were weighed and homogenized in 500 ml distilled water, then 400 mg faecal
`homogenate was placed in a quartz boat and burnt in a Beckman Biological Material
`Oxidiser. The carbon - 14 dioxide produced was trapped in 15 ml of a basic scintill-
`ation cocktail (Harvey Corporation). The cocktail was then counted and corrected
`for quenching. All samples were analyzed in duplicate. Urine and faeces radioactivity
`was expressed as a percentage of the dose administered.
`
`Results
`Serum levels
`The serum levels of tiemonium iodide after the 50 mg labelled capsule are shown for
`the 5 subjects in Figure 2. Similarly, the serum levels for the 4 subjects taking
`tiemonium methosulphate are shown in Figure 3.
`ttrade mark, CERM
`
`1 3 3
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`Human studies on the bioavailability of a quaternary ammonium compound, tiemonium iodide
`and tiemonium methosulphate
`
`Figure 2. Serum levels of 14C tiemoniurn iodide in 5 normal volunteers after oral administration
`
`Subject A
`
`240 r.
`
`Subject B
`240 [
`
`”
`
`1
`
`2
`
`6
`5
`4
`3
`Time (hours )
`
`7
`
`8
`
`
`
`1
`
`2
`
`6
`5
`4
`3
`Time (hours )
`
`7
`
`8
`
`
`
`Subject D
`240 r
`
`v)
`
`Subject C
`.
`240 r
`C ‘2 200
`8 160
`.- .c.
`E 120
`2 ._
`80’
`6 4 0
`
`v)
`
`Subject E
`240 r
`
`Time (hours)
`
`Time (hours)
`
`Various pharmacokinetic parameters were calculated for each salt of tiemonium,
`1
`using a two compartment model : C(t) = FD - {Ka - [exp. (-ke(t-1)-exp. (-ka(t-1)],
`V Ka-Ker
`where C(t) is the concentration at time t, in hours, Ka is the absorption rate constant,
`Ke is the elimination rate constant, and 1 is the lag time. The computer programme
`provided values for the lag time, the time from swallowing the capsule until some of
`the drug was absorbed into the systemic circulation, the absorption half-life, and the
`
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`I. T. Scoular, Anne Monks, C. Burgess and P. Turner
`
`Figure 3.
`Serum levels of 4C tiemonium methosulphate in 4 normal volunteers after oral
`administration
`
`Subject F
`240 1
`
`L
`
`Subject G
`240 r
`-
`200
`160.
`120-
`
`Time (hours )
`
`Time (hours)
`
`Subject H
`240 [
`
`Subject J
`240 [
`
`Time (hours )
`
`Time (hours)
`
`elimination half-life. In 2 subjects, a negative lag time was calculated. For these
`subjects, a lag time of zero was assumed and the computer recalculated using the
`1
`FD J Ka
`(exp. (-ket)-exp (-kat)].
`model: C(t) =-
`-.
`V IKa-KeI
`Computer drawn decay curves showing the rate of elimination of the tiemonium
`iodide following intravenous injection are shown in Figure 4.
`The results for both routes of administration are summarized in Table I. By using
`the method of Shand et a1.,* the percentage of tiemonium absorbed was calculated
`as 6%.
`
`Urinary levels
`The percentage of the dose excreted in the 24-hour collection periods was calculated,
`enabling an approximate value for the urinary excretion half-life to be calculated by
`a linear regression analysis (Table 11).
`
`Faecal excretion
`Table 111 gives the percentage of the dose of either salt of tiemonium, given by the
`oral and intravenous route, excreted over a total of 72 hours.
`
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`Human studies on the bioavailability of a quaternary ammonium compound, tiemonium iodide
`and tiemonium methosulphate
`
`Figure 4. Serum levels of I4C tiemonium iodide in 3 normal volunteers after intravenous
`administration
`
`Subject B
`.
`lo00
`c 3 800
`-
`2
`2 600
`E
`b 400
`u C
`B
`z 200
`0 1 2 3 4 5 6 7 8 9 1011 12
`Time (hours)
`
`Subject J
`
`Subject C
`
`1 2 3'4 5 6 7 8 9 101112
`Time (hours)
`
`Time (hours)
`
`Table I. Serum pharmacokinetic data for 2 salts of tiemonium
`Lag time
`Subject
`Absorption
`@-'I
`half-life (h-1)
`Oral - fiemnium iodide
`A
`0.3
`B
`0.4
`c
`0.1
`0
`D
`I3
`0
`Oral - tiemonium methosulphate
`F
`0.4
`0.4
`G
`H
`0.2
`J
`0.4
`Intravenous - tiemonium iodide
`0
`B
`C
`0
`J
`0
`
`0.4
`0.9
`0.7
`1.4
`0.8
`
`0.1
`1.1
`1.6
`0.1
`
`0.1
`0.1
`0.1
`
`136
`
`Elimination
`half-life (h-1)
`
`2.6
`1 .o
`2.6
`3.5
`2.9
`
`3.7
`1.3
`2.0
`10.6
`
`0.6
`1 .o
`1.6
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`
`I. T. Scoular, Anne Monks, C. Burgess and P. Turner
`
`Table 11.
`route only
`Subject
`
`Tiemonium iodide
`A
`B
`C
`D
`E
`Tiemonium methosulphate
`F
`G
`H
`J
`
`Urinary excretion data from volunteers administered 2 salts of tiemonium by the oral
`
`Urine
`half-life (h- l )
`
`7.6
`6.9
`6.0
`Incomplete
`7.3
`
`7.0
`8.4
`26.4
`9.7
`
`04 dose excreted
`in 24 hours
`
`4.5
`18.6
`10.9
`3.7
`6.1
`
`4.4
`8.5
`3.2
`8.0
`
`Table III. Faecal excretion data from volunteers administered 2 salts of tiemonium
`% dose excreted in faeces
`Subject
`over 72 hours
`
`Oral - tiemonium iodide
`A
`B
`C
`D
`E
`Oral - tiemonium methosulphate
`F
`G
`H
`J
`Intravenous - tiemonium iodide
`J
`
`19.3
`Incomplete
`86.6
`61.1
`90.6
`
`77.2
`Incomplete
`41.8
`97.9
`
`11.4
`
`Discussion
`The poor absorption of quaternary ammonium compounds in man has been
`recognized for a number of years.2,3-6,9 The maximum absorption of labelled
`butylscopolamine mainly from the upper small intestine has been reported as 10 %
`of the dose admini~tered.~*g This poor absorption has, to date, made measurement
`of serum drug levels impossible, because the serum radioactive levels have not been
`significantly different from background. In the present study, it was possible to
`follow serum drug levels up to 8 hours after the administration of the radioactive
`dose. However, only small numbers of volunteers were used in each group since
`consideration was given to the ethics of radioactive studies. The pharmacokinetic
`profile was similar with both salts of tiemonium, though there was considerable
`variability in individuals peak serum levels.
`Urinary excretion was very low because of the poor absorption of the drug. In
`the first 24 hours, approximately 8 % of either salt of tiemonium was excreted after
`
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`
`Human studies on the bioavailability of a quaternary ammonium compound, tiemonium iodide
`and tiemonium methosulphate
`
`oral administration, and after 72 hours virtually all the absorbed drug had been
`eliminated. Similarly very low values for the urinary excretion of butylscopolamine
`have been reported.3-9
`After oral administration, a large percentage of the dose of either salt of
`tiemonium was recovered from the faeces. This was the unabsorbed drug, amounting
`to approximately 70 % of the dose administered over 72 hours. It is possible that an
`incomplete recovery of the labelled drug from the faeces accounts for the low values
`found. A longer collection period might have resulted in a greater recovery from the
`faeces, since this class of drug is known to bind strongly to the wall of the upper
`intestine. Since only 6% of the dose of tiemonium administered was absorbed, it
`would seem that the therapeutic effect may be due to a local direct action on the
`intestine wall, as has been suggested for butyl~copolamine.~,9 The percentage of the
`dose recovered after intravenous injection presumably reflects biliary excretion of
`tiemonium. Other routes of excretion, e.g. expiratory air and the skin, must also be
`considered. The total urinary and faecal excretion of tiemonium over 72 hours was
`about 80 %.
`In conclusion, since the absorption and excretion of the iodide and methosulphate
`salts of tiemonium appear to be similar, the bioavailability of these two salts is of
`the same order.
`
`Acknowledgements
`We wish to thank CERM, Riom, France for supplies of tiemonium iodide and methosulphate.
`Acknowledgement is given to the Occupational Health Service of the Post Office and volunteers
`from the East Central District Office, King Edward Building, London, E.C.l for their co-operation.
`References
`1 . Beau, P. G., Constantin, M., Talvard, J., and Duchene-Marullaz, P., (1968). Elimination de
`l’iodure de tiemonium radioactif et essai de recherche des mktabolites, chez le rat et la souris.
`Therapie, 23,399-409.
`2. Beerman, B., Hellstrom, K., and Rosen, A., (1971). The gastro-intestinal absorption of anti-
`cholinergic drugs: comparison between individuals. Acfa Phurmacol. Toxic01 (Kbh.), 29,98-102.
`3. Hellstrom, K., Rosen, A., and Soderlund, K., (1970). The gastro-intestinal absorption and the
`excretion of H3-butylscopolamine (hyoscine butylbromide) in man. Scand. J. Gastroenferof.,
`5, 585-592.
`4. Herxheimer, A., and Haefeli, L., (1966). Human pharmacology of hyoscine butylbromide.
`Lancet, 2,418-421.
`5. Levine, R. M., and Clark, B. B., (1955). The biotransformation, excretion and distribution
`of the anticholinergic quaternary ammonium compound benzomethamine (MC 3 199) and its
`tertiary amine analog (MC 3137) and related compounds in animals. J. Pharmacol. Exp. Ther.,
`114, 63-77.
`6. Moller, J., and Rosen, A., (1968). Comparative studies on parenteral and oral effective doses
`of anticholinergic drugs. Acfa Med. Scund., 184,201-209.
`7. Pentikainen, P., Penttila, A., Vapaatalo, H., and Hackman, R., (1973). Intestinal absorption,
`intestinal distribution and excretion of (1 “C) labelled hyoscine N-butylbromide (butylscopolamine)
`in the rat. J. Pharm. Pharmacol., 25,371-375.
`8. Shand, D. G., Nuckolls, E. M., and Oates, J. A., (1970). Plasma propranolol levels in adults
`with observations in four children. Clin. Pharmacol. Ther., 11, 112-120.
`9. Vapaatalo, H., Pentilla, A., and Kaltiala, A., (1975). The absorption and elimination of orally
`administered (1°C) hyoscine N-butylbromide (butylscopolamine). J. Pharm. Pharmucol., 27,542-
`543.
`
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