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BIOAVAILABILITY AFTER INTRAMUSCULAR INJECTION
693 closed mitral valvotomy, some on more than one occasion. In 44 in whom pulmonary vascular resistance was measured, 32 had a resistance between 1 and 5 units, 9 between 5 and 10 units, and 3 in excess of 10 units. The use of postoperative pharmacological inotropic support has also decreased considerably; in many patients it is not used at all, indicating better myocardial function. The superiority of one valve over another will be determined primarily by long-term results, where durability and thromboembolic complication-rates are the most important factors. Department of Cardiothoracic Surgery, St. Bartholomew’s Hospital, London EC1A 7BE
GARETH REES
BIOAVAILABILITY AFTER INTRAMUSCULAR
INJECTION SIR,-You state1 that: "In essence absorption is favoured by
liposolubility, high concentration, and low molecular weight; it is reduced by ionisation and by water solubility". Since good liposolubility of organic drug substances is in general accompanied by water insolubility and since ionisation in general results in water solubility, we feel that the above statement is a contradiction in terms. The question remains-is the bioavailability of a drug after intramuscular (i.m.) injection favoured by liposolubility or by water solubility? The results of our comparative study of the bioavailability after intravenous (i.v.) injection versus i.m. injection of the anticholinergic drug thiazinamium methylsulphate (’Multergan’) are of interest in this context. Thiazinamium methylsulphate is a phenothiazine derivative with a quaternary ammonium group in the molecule. This group plays a dominant role in the physicochemical properties of the drug: it is completely ionised, which results in a good water solubility at all pH values. Seven patients received a dose of thiazinamium methylsulphate equal to 6.25 mg of the base. The i.v. injection was given in the cubital vein and a few days later an i.m. injection was given in the thigh. Blood-samples were drawn at 3, 6,10, 15, 20, 30, 45, 60, 75, 90, 105, and 120 min after injection, and plasma concentrations were measured.2 The figure shows that after i.v. injection plasma concentrations are high at first, but fall away rapidly, resulting in a halflife of about 20 min in the &bgr;-phase. After 120 min almost all of the drug has disappeared from the plasma. After i.m. injection the peak in the concentration time appears very quickly (after 6 min). After the peak, concentrations fall rapidly and again the half-life is about 20 min in the p-phase. Bioavailability (during these 120 min) after i.m. injection was 100%. We conclude that absorption of this ionised, water-soluble drug from the site of injection is complete and very rapid. The peak plasma concentration appears much sooner than with, for
after 1-2 h) which is also soluble. This may be caused by the relative small molecular weight of thiazinamium cation (300) compared with the streptomycin cation (582). Results with other quaternary ammonium compounds34 also indicate a rapid absorption from the site of injection. These findings suggest that solubility in the interstitial fluid is of prime importance for rapid absorption, as suggested in some studies with poorly water-soluble drugs mentioned in your editorial.5-8 The question how i.m. injected drugs gain access to the general circulation remains unanswered, but our findings with ionised, water-soluble drugs indicate that neither lipid insolubility nor the small amount of pores in the membrane are rate-limiting factors. Finally, our results carry a warning about the safety of i.m. injections. The very rapid absorption that can occur with some drugs results in high plasma concentrations immediately after administration; this may give rise to substantial side-effects (e.g., tachycardia with thiazinamium).
example, streptomycin (maximum water
J. H. G. JONKMAN
Medical Department and Department of Pharmaceutical and Analytical Chemistry, State University, Groningen 8004, Netherlands
L. E. VAN BORK R. A. DE ZEEUW N. G. M. ORIE
MILK AND FLUORIDE
SIR,-Dr Shattock (Feb. 7, p. 301) puts a high value on children’s milk, but why does he exaggerate the costs? Those he cites are much higher than what the Government pays for school and welfare milk (see Dairy Facts and Figures from the Milk Marketing Board). Those who have benefited from these schemes now represent about half the total population, and this expenditure on milk for children must have saved the nation many millions of pounds in medical treatment. ’Dentamilk’ is the name we give to milk which is both pasteurised and fluoridised. Milk contains 13% of the natural elements of the nutrients necessary to promote tooth and bone growth. When its water content is fluoridised, it protects children’s teeth from caries. This Foundation is a non-profitmaking charity. The leaflet to which Dr Shattock refers was not circulated as a commercial venture but to promote a public-health measure. The addition of 14 500 tons of fluoride to public water supplies means that during the normal human lifespan a million tons of fluoride would be used, a wasteful procedure. Selective fluoridation removes fears of possible harmful effects to susceptible subjects and overcomes objections to compulsory medication. It avoids excessive use of an indestructible toxic chemical. The World Health Organisation recommends trials of selective fluoridation in countries which have no piped water (about 75% of the world’s population). Only 8.6% of Britain’s population drink fluoridated water. Selective fluoridation can be used everywhere at a fraction of the cost of water fluoridation. Surely this is a more scientific, way of preventing dental caries. Borrow Dental Milk Foundation, Lister House, 11 & 12 Wimpole Street, London W1M 7AB
economic, and acceptable
MAXWELL BRESLER
1. Lancet, 1975, i, 261. 2. Jonkman, J. H. G., Wijsbeek, J., Hollenbeek Brouwer-de Boer, S., De Zeeuw, R. A., van Bork, L. E., Orie, N. G. M. J. Pharm. Pharmac. 1975,
27, 849.
Plaema concentrations (ng/ml) after i.v. of6-25 mg thiazinamium methylsulphate
(left) and i.m. (right) injection (mean of seven patients).
3. Sundwall, A., Vessman, J., Strindberg, B. Eur. J. clin. Pharm. 1973, 6, 191. 4. Möller, J., Rosén, A. Acta med. scand. 1968, 184, 201. 5. Greenblatt, D. J., Shader, R. I., Koch-Weser, J. New Engl. J. Med. 1974, 291, 1116. 6. Hillestad, L., Hansen, T., Melson, H., Drivenes, A. Clin. Pharmac. Ther. 1974, 16, 479. 7. Karlsson, E., Collste, P., Rawlins, M. D. Eur. J. clin. Pharmac. 1974, 7, 455. 8. Wilder, B. J., Serrana, E. E., Ramsey, E., Buchanan, R. A. Clin. Pharmac. Ther. 1974, 16, 507.
GARETH REES
BIOAVAILABILITY AFTER INTRAMUSCULAR
INJECTION SIR,-You state1 that: "In essence absorption is favoured by
liposolubility, high concentration, and low molecular weight; it is reduced by ionisation and by water solubility". Since good liposolubility of organic drug substances is in general accompanied by water insolubility and since ionisation in general results in water solubility, we feel that the above statement is a contradiction in terms. The question remains-is the bioavailability of a drug after intramuscular (i.m.) injection favoured by liposolubility or by water solubility? The results of our comparative study of the bioavailability after intravenous (i.v.) injection versus i.m. injection of the anticholinergic drug thiazinamium methylsulphate (’Multergan’) are of interest in this context. Thiazinamium methylsulphate is a phenothiazine derivative with a quaternary ammonium group in the molecule. This group plays a dominant role in the physicochemical properties of the drug: it is completely ionised, which results in a good water solubility at all pH values. Seven patients received a dose of thiazinamium methylsulphate equal to 6.25 mg of the base. The i.v. injection was given in the cubital vein and a few days later an i.m. injection was given in the thigh. Blood-samples were drawn at 3, 6,10, 15, 20, 30, 45, 60, 75, 90, 105, and 120 min after injection, and plasma concentrations were measured.2 The figure shows that after i.v. injection plasma concentrations are high at first, but fall away rapidly, resulting in a halflife of about 20 min in the &bgr;-phase. After 120 min almost all of the drug has disappeared from the plasma. After i.m. injection the peak in the concentration time appears very quickly (after 6 min). After the peak, concentrations fall rapidly and again the half-life is about 20 min in the p-phase. Bioavailability (during these 120 min) after i.m. injection was 100%. We conclude that absorption of this ionised, water-soluble drug from the site of injection is complete and very rapid. The peak plasma concentration appears much sooner than with, for
after 1-2 h) which is also soluble. This may be caused by the relative small molecular weight of thiazinamium cation (300) compared with the streptomycin cation (582). Results with other quaternary ammonium compounds34 also indicate a rapid absorption from the site of injection. These findings suggest that solubility in the interstitial fluid is of prime importance for rapid absorption, as suggested in some studies with poorly water-soluble drugs mentioned in your editorial.5-8 The question how i.m. injected drugs gain access to the general circulation remains unanswered, but our findings with ionised, water-soluble drugs indicate that neither lipid insolubility nor the small amount of pores in the membrane are rate-limiting factors. Finally, our results carry a warning about the safety of i.m. injections. The very rapid absorption that can occur with some drugs results in high plasma concentrations immediately after administration; this may give rise to substantial side-effects (e.g., tachycardia with thiazinamium).
example, streptomycin (maximum water
J. H. G. JONKMAN
Medical Department and Department of Pharmaceutical and Analytical Chemistry, State University, Groningen 8004, Netherlands
L. E. VAN BORK R. A. DE ZEEUW N. G. M. ORIE
MILK AND FLUORIDE
SIR,-Dr Shattock (Feb. 7, p. 301) puts a high value on children’s milk, but why does he exaggerate the costs? Those he cites are much higher than what the Government pays for school and welfare milk (see Dairy Facts and Figures from the Milk Marketing Board). Those who have benefited from these schemes now represent about half the total population, and this expenditure on milk for children must have saved the nation many millions of pounds in medical treatment. ’Dentamilk’ is the name we give to milk which is both pasteurised and fluoridised. Milk contains 13% of the natural elements of the nutrients necessary to promote tooth and bone growth. When its water content is fluoridised, it protects children’s teeth from caries. This Foundation is a non-profitmaking charity. The leaflet to which Dr Shattock refers was not circulated as a commercial venture but to promote a public-health measure. The addition of 14 500 tons of fluoride to public water supplies means that during the normal human lifespan a million tons of fluoride would be used, a wasteful procedure. Selective fluoridation removes fears of possible harmful effects to susceptible subjects and overcomes objections to compulsory medication. It avoids excessive use of an indestructible toxic chemical. The World Health Organisation recommends trials of selective fluoridation in countries which have no piped water (about 75% of the world’s population). Only 8.6% of Britain’s population drink fluoridated water. Selective fluoridation can be used everywhere at a fraction of the cost of water fluoridation. Surely this is a more scientific, way of preventing dental caries. Borrow Dental Milk Foundation, Lister House, 11 & 12 Wimpole Street, London W1M 7AB
economic, and acceptable
MAXWELL BRESLER
1. Lancet, 1975, i, 261. 2. Jonkman, J. H. G., Wijsbeek, J., Hollenbeek Brouwer-de Boer, S., De Zeeuw, R. A., van Bork, L. E., Orie, N. G. M. J. Pharm. Pharmac. 1975,
27, 849.
Plaema concentrations (ng/ml) after i.v. of6-25 mg thiazinamium methylsulphate
(left) and i.m. (right) injection (mean of seven patients).
3. Sundwall, A., Vessman, J., Strindberg, B. Eur. J. clin. Pharm. 1973, 6, 191. 4. Möller, J., Rosén, A. Acta med. scand. 1968, 184, 201. 5. Greenblatt, D. J., Shader, R. I., Koch-Weser, J. New Engl. J. Med. 1974, 291, 1116. 6. Hillestad, L., Hansen, T., Melson, H., Drivenes, A. Clin. Pharmac. Ther. 1974, 16, 479. 7. Karlsson, E., Collste, P., Rawlins, M. D. Eur. J. clin. Pharmac. 1974, 7, 455. 8. Wilder, B. J., Serrana, E. E., Ramsey, E., Buchanan, R. A. Clin. Pharmac. Ther. 1974, 16, 507.