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Prediction of Drug Distribution into Human Milk from Physicochemical Characteristics

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Summary

Decisions about the safety of breast feeding during maternal ingestion of drugs require knowledge of the amount of drug which might be present in the milk. For many drugs this has not been studied, and mothers are usually advised against breast feeding. In many cases this is undoubtedly unnecessary, as the total dose to which the baby is exposed is often negligible. It would be very helpful, therefore, to be able to predict the approximate amount of drug which might be present in milk.

Existing theory of pH partitioning enables estimation of the distribution of unbound drug. i.e. milk: plasma unbound ratios. However, these ratios are poor estimates of the concentration ratios for whole milk, because whole milk contains proteins and lipid in which drugs will distribute in amounts which depend on their particular physicochemical properties.

To predict the milk: plasma concentration ratios for whole milk, the amount of drug present in the protein and lipid phases must be considered along with the unbound drug distribution. A ‘phase distribution model’ has therefore been developed which permits estimation of whole milk: plasma concentration ratios.

The model requires a knowledge of the unbound drug concentration ratio, the plasma and milk unbound fractions and the milk lipid: ultrafiltrate partition coefficient. Evaluation of the model by comparison of predicted whole milk ratio values with literature milk: plasma area under the curve (AUC) ratios indicated a trend to overprediction for acidic and neutral drugs and underprediction for basic drugs. Transformation of the phase distribution equation by taking logarithms results in a relationship which can be analysed by multiple linear regression to derive predictive equations for acidic and basic drugs which take into account the relative contributions of each component of the model. Regression of the logarithms of the literature milk: plasma AUC values against the independent variables resulted in good correlations for acidic and basic drugs. The independent variables explained 93.1% and 82.9% of the variance in the values for acidic and basic drugs, respectively, with random scatter of residuals.

The equations, together with those to predict unbound fractions of drug in milk and milk lipid: ultrafiltrate partition coefficients, enable the ratio of the milk: plasma AUCs to be estimated for any acidic or basic drug for which the distribution into human milk is not known, using the pKa, octanol: water partition coefficient and plasma protein binding values of the drug. The data set for neutral drugs (n = 3) was too small to develop a correlation equation.

The predicted milk: plasma ratio of the 2 AUCs enables the infant dose rate to be calculated using the measured or estimated maternal steady-state plasma concentration and the volume of milk ingested.

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References

  • Albert A, Sergeant EP. Ionisation constants of acids and bases. pp. 12–13, Methven, London. 1962

    Google Scholar 

  • American Society of Hospital Pharmacists. Drug Information ′87. p. 169. American Society of Hospital Pharmacists, Bethesda. 1987a

    Google Scholar 

  • American Society of Hospital Pharmacists. Drug Information ′87. p. 408. American Society of Hospital Pharmacists, Bethesda. 1987b

    Google Scholar 

  • Anderson P, Bonbesson U, Mattiasson I, Johansson BW. Verapamil and norverapamil in plasma and breast milk during feeding. European Journal of Clinical Pharmacology 31: 625–627, 1987

    Article  PubMed  CAS  Google Scholar 

  • Ansell C. Moore A. Barrie H. Electrolyte and pH changes in human milk. Pediatric Research 11: 1177–1179. 1977

    Article  PubMed  CAS  Google Scholar 

  • Atkinson HC, Begg EJ. Relationship between human milk lipid: ultrafiltrate and octanol: water partition coefficients. Journal of Pharmaceutical Sciences 77: 796–798, 1988a

    Article  PubMed  CAS  Google Scholar 

  • Atkinson HC, Begg EJ. Prediction of drug concentrations in human skim milk from plasma protein binding and acid-base characteristics. British Journal of Clinical Pharmacology 25: 495–503, 1988b

    Article  PubMed  CAS  Google Scholar 

  • Atkinson HC, Begg EJ, Darlow BA. Drugs in human milk. Clinical Pharmacokinetics 14: 217–240, 1988

    Article  PubMed  CAS  Google Scholar 

  • Australian National Drug Information Service. Oxprenolol drug profile. Australian Health Department. Woden, ACT. 1987

  • Barber HE, Gabrielle M, Hawksworth NR, Kitteringham NR, Petersen J, et al. Protein binding of atenolol and propranolol to human serum albumin and human plasma. British Journal of Clinical Pharmacology 6: 446–447, 1978

    Article  Google Scholar 

  • Bauer J, Paper B, Zajicek J, Groshong T. Propranolol in human plasma and breast milk. American Journal of Cardiology 43: 860, 1979

    Article  PubMed  CAS  Google Scholar 

  • Bitzen PO, Gustafsson KG, Melander A, Wahlin-Boll E. Excretion of paracetamol in human breast milk. European Journal of Clinical Pharmacology 20: 123–125, 1981

    Article  PubMed  CAS  Google Scholar 

  • Blinick G, Inturrisi CE, Jerez E, Wallach RC. Methadone assays in pregnant women and progency. American Journal of Obstetrics and Gynecology 121: 617–621, 1975

    PubMed  CAS  Google Scholar 

  • Bowman WC, Rand MJ. Textbook of pharmacology. 2nd ed., Blackwell Scientific Publications, Oxford, 1980

    Google Scholar 

  • Brandt R. Passage of diazepam and desmethyldiazepam into breast milk. Arzneimettel-Forschung 26: 454–457, 1976

    CAS  Google Scholar 

  • Brogden RN, Heel RC. Aztreonam: a review of its antibacterial activity, pharmacokinetics properties and therapeutic use. Drugs 31: 96–130, 1986

    Article  PubMed  CAS  Google Scholar 

  • Chaffman M, Brodgen RN. Diltiazem: a review of its pharmacological properties and therapeutic efficacy. Drugs 29: 387–454, 1985

    Article  PubMed  CAS  Google Scholar 

  • Chaikin P, Chasin M, Kennedy B, Silverman B. Suprofen concentrations in human breast milk. Journal of Clinical Pharmacology 23: 385–390, 1983

    PubMed  CAS  Google Scholar 

  • Chan V, Tse TF, Wong V. Transfer of digoxin across the placenta and into breast milk. British Journal of Obstetrics and Gynaecology 85: 605–609, 1978

    Article  PubMed  CAS  Google Scholar 

  • Cooke I, Back D, Shroff N. Norethisterone concentration in breast milk and infant and maternal plasma during ethynodiol di-acetate administration. Contraception 31: 611–621, 1985

    Article  PubMed  CAS  Google Scholar 

  • Cornford EM, Braun LD, Olendorf WH. Hill MA. Comparison of lipid-mediated blood-brain-barrier penetrability in neonates and adults. American Journal of Physiology 243: C181–C186. 1982

    Google Scholar 

  • Devlin RG, Duchin KL, Fleiss PM. Nadalol in human serum and breast milk. British Journal of Clinical Pharmacology 12: 393–396, 1981

    Article  PubMed  CAS  Google Scholar 

  • Drayer DE. Clinical consequences of the lipophilicity and plasma protein binding of anti-arrhythmic drugs and active metabolites in man. Annals of the New York Academy of Sciences 432: 45–56, 1984

    Article  PubMed  CAS  Google Scholar 

  • Evans GH, Shand DG, Disposition of propranolol VI. Independent variation in steady state circulating drug concentrations and half life as a result of plasma drug binding in man. Clinical Pharmacology and Therapeutics 14: 494–500, 1973

    PubMed  CAS  Google Scholar 

  • Ferris AM, Jensen RG. Lipids in human milk: a review. 1: sampling, determination and content. Journal of Pediatrie Gastro-enterology and Nutrition 3: 103–122, 1984

    Google Scholar 

  • Fidler J, Smith V, De Swiet M. Excretion of oxprenolol and timolol in breast milk. British Journal of Obstetrics and Gynaecology 90: 961–965, 1983

    Article  PubMed  CAS  Google Scholar 

  • Findlay JWA, Butz R, Sailstad J, Warren J, Welch R. Pseudoe-phedrine and tripolidine in plasma and breast milk of nursing mothers. British Journal of Clinical Pharmacology 18: 901–906, 1984

    Article  PubMed  CAS  Google Scholar 

  • Findlay JWA, Deangelis RL, Kearney MF, Welch RM, Findlay JM. Analgesic drugs in breast milk and plasma. Clinical Pharmacology and Therapeutics 29: 625–633, 1981

    Article  PubMed  CAS  Google Scholar 

  • Fleiss PM, Richwald J, Gordon J, Stern M, Frantz M, et al. Azirconam in human serum and breast milk. British Journal of Clinical Pharmacology 19: 509–551, 1985

    Article  PubMed  CAS  Google Scholar 

  • Freese E, Levin BC, Pearce R, Sreevalsan T, Kaufman JJ, et al. Correlation between the growth inhibitory effects, partition coefficients and teratogenic effects of lipophilic acids. Teratology 20: 413–440, 1979

    Article  PubMed  CAS  Google Scholar 

  • Goodman-Gilman A. Goodman LS. Rall TW. Murad F (Eds). The pharmacological basis of therapeutics. 7th ed., pp. 1668–1713, MacMillan, New York. 1985

    Google Scholar 

  • Gray MS, Kane P, Squires S. Further observations on metronidazole (Flagyl). British Journal of Venereal Diseases 37: 278–279, 1961

    PubMed  CAS  Google Scholar 

  • Greenblatt DJ, Allen MD, Hamatz JS, Slader RI. Diazepam disposition determinants. Clinical Pharmacology and Therapeutics 27: 301–312, 1980

    Article  PubMed  CAS  Google Scholar 

  • Hansch C. Experimental determination of partition coefficients. In Purcell et al. (Eds) Strategy to drug design: a guide to biological activity, pp. 126–143, Wiley, New York. 1973

    Google Scholar 

  • Hansch C. Leo A. Substituent constants for correlation analysis in chemistry and biology, pp 171–329, J. Wiley & Sons, New York. 1979

    Google Scholar 

  • Harrison VC, Peat G. Significance of milk pH in new born infants. British Medical Journal 4: 515–518, 1972

    Article  PubMed  CAS  Google Scholar 

  • Heisterberg L, Branebjerg P. Blood and milk concentrations of metronidazole in mothers and infants. Journal of Perinatal Medicine 11: 114–120, 1983

    Article  PubMed  CAS  Google Scholar 

  • Hocking RR. The analysis and selection of variables in linear regression. Biometrics 32: 1–49, 1976

    Article  Google Scholar 

  • Ilium L, Bundegaard H, Davis SS. A constant partition model for examining the sorption of drugs by plastic infusion bags. International Journal of Pharmaceutics 17: 183–192, 1983

    Article  Google Scholar 

  • Inoue H. Unno N. Ou MC. Sugimoto T. Level of verapamil in human milk. European Journal of Clinical Pharmacology 26: 657. 1984

    Article  PubMed  CAS  Google Scholar 

  • Jensen RG, Clark RM, Ferris AM. Composition of the lipids in human milk: a review. Lipids 15: 345–355, 1980

    Article  PubMed  CAS  Google Scholar 

  • Johns D, Rutherford L, Leighton P, Vogel C. Secretion of methotrexate in human milk. American Journal of Obstetrics and Gynaecology 112: 978–980, 1972

    CAS  Google Scholar 

  • Judis J. Binding of codeine, morphine and methadone to human serum proteins. Journal of Pharmaceutical Sciences 66: 802–805, 1977

    Article  PubMed  CAS  Google Scholar 

  • Kafetzis DA, Brater DC, Fanourgakis JE, Voyatzis J, Georga-kopoulos P. Ceftriaxone distribution between maternal blood and fetal blood and milk postpartum. Antimicrobial Agents and Chemotherapy 23: 870–873, 1983

    Article  PubMed  CAS  Google Scholar 

  • Kaneko S, Sato T, Suzu K. The levels of anticonvulsants in breast milk. British Journal of Clinical Pharmacology 7: 624–627, 1979

    Article  PubMed  CAS  Google Scholar 

  • Kesaneimi YA. Peripheral blood of lactating women after ethanol administration. Journal of Obstetrics and Gynaecology (British Commonwealth) 81: 84–86, 1974

    Article  Google Scholar 

  • Keotsawang S. Injected long-acting medroxyprogesterone acetate effect on human milk and concentations in milk. Journal of the Medical Association of Thailand 60: 57–60, 1977

    Google Scholar 

  • Kuhnz W, Koch S, Jakob S, Hartman A, Helge H, et al. Ethosuximide in epileptic women during pregnancy and lactation period. Placental transfer, serum concentrations in nursed infants and clinical status. British Journal of Clinical Pharmacology 18: 671–677, 1984

    Article  PubMed  CAS  Google Scholar 

  • Kulas J. Lunell NO. Rosing U. Steen B. Rane A. Atenolol and metoprol. A comparison of their excretion into human breast milk. Acta Obstetrica et Gynaecologica Scandavinica 118 (Suppl.): 65–69, 1984

    Article  CAS  Google Scholar 

  • Levin VA. Relationship of octanol: water partition coefficient and molecular weight to rat brain capillary permeability. Journal of Medicinal Chemistry 23: 682–684, 1980

    Article  PubMed  CAS  Google Scholar 

  • Levin VA, Dolginow D, Londahl HD, Torke C, Csejtey J. Relationship of octanol: water partition coefficient and molecular weight to cellular permeability and partitioning in S49 lymphoma cells. Pharmaceutical Research 6: 259–266, 1984

    Article  Google Scholar 

  • Levitan A. Manion J. Propranolol therapy during pregnancy and lactation. American Journal of Cardiology 32: 247, 1973

    PubMed  CAS  Google Scholar 

  • Lewis A, Johnston A, Patel L, Turner P. Mexilitene in human blood and breast milk. Postgraduate Medical Journal 57: 546–547, 1981

    Article  PubMed  CAS  Google Scholar 

  • Lieb WR. Stein WB. The molecular basis of simple diffusion within biological membranes. In Bronner & Kleinzeller (Eds) Current topics in membranes and transport. Vol. 2. pp. 1–39, Academic Press, New York, 1971

    Google Scholar 

  • Liedholm HA, Melander PO, Bitzen G, Helm G, Lonnerholm I, et al. Accumulation of atenolol and metoprolol in human breast milk. European Journal of Clinical Pharmacology 20: 229–231, 1981

    Article  PubMed  CAS  Google Scholar 

  • Lonnerdal B, Forsum E, Hambraeus L. A longitudinal study of the protein, nitrogen and lactose contents of human milk from Swedish well nourished mothers. American Journal of Clinical Nutrition 29: 1127–1133, 1976

    PubMed  CAS  Google Scholar 

  • Lunde PKM, Rane A, Yaffe SJ, Lund L, Sjoqvist F. Plasma protein binding of diphenylhydantoin in man. Clinical Pharmacology and Therapeutics 11: 846–855, 1970

    PubMed  CAS  Google Scholar 

  • Magdon E. Untersuchungen zur Wirkung von 4-Nitroimidazole (Isometronidazol) auf die strahlenbedingte Waschtumschemmung und Heilungstrate von Transplantationstumoren. Radiobiologia Radiotherapia (Berlin) 26: 351–358, 1985

    CAS  Google Scholar 

  • Matheson I, Samseth M, Loberg R, Faegri A, Prentice A. Milk transfer of phenoxymethylpenicillin during puerperal mastitis. British Journal of Clinical Pharmacology 25: 33–40, 1988

    Article  PubMed  CAS  Google Scholar 

  • Matsuda S. Transfer of antibiotics into maternal milk. Biological Research in Pregnancy 5: 57–60, 1984

    CAS  Google Scholar 

  • Meskin MS, Lien EJ. QSAR analysis of drug excretion into human breast milk. Journal of Clinical and Hospital Pharmacy 10: 269–278, 1985

    PubMed  CAS  Google Scholar 

  • Miller GE, Banerjee NC, Stowe CM. Diffusion of certain weak organic acids and bases across the bovine mammary gland membrane after systemic administration. Journal of Pharmacology and Experimental Therapeutics 157: 245–253, 1967

    PubMed  CAS  Google Scholar 

  • Mischief TW, Corson SL, Larranaga A, Bolognese RJ, Neiss ES, et al. Cephradine and epicillin body fluids of lactating and pregnant women. Journal of Reproductive Medicine 21: 130–136, 1978

    Google Scholar 

  • Moffat AG (Ed). Clarke’s isolation and identification of drugs. 2nd ed., pp 309–1069, Pharmaceutical Press, London, 1986

    Google Scholar 

  • Newton DW, Kluza RB. pKa values of medicinal compounds in pharmacy practice. Drug Intelligence and Clinical Pharmacy 12: 546–554, 1978

    CAS  Google Scholar 

  • Ochs HR, Knuchel M. Pharmacokinetics and absolute bioavailability of diltiazem in humans. Klinische Wochenschrift 62: 303–306, 1984

    Article  PubMed  CAS  Google Scholar 

  • Okada M, Inoue H, Nakamura U, Kishimoto M. Excretion of diltiazem in human milk. New England Journal of Medicine 312: 992–993, 1985

    Article  PubMed  CAS  Google Scholar 

  • Ost L, Wettrell G, Bjorkhem I, Rane A. Prednisolone excretion in human milk. Journal of Pediatrics 106: 1008–1011, 1985

    Article  PubMed  CAS  Google Scholar 

  • Pharmaceutical Society of Great Britain. The pharmaceutical codex. 11th ed., Pharmaceutical Press, London, 1979

    Google Scholar 

  • Pittard WB, O’Neill W. Amitriptyline excretion in human milk. (Letter). Journal of Clinical Psychopharmacology 6: 383–384, 1986

    Article  PubMed  Google Scholar 

  • Plomp TA, Thiery M, Maes RAA. The passage of thiamphenicol and chloramphenicol after single and repeated oral administration. Veterinary and Human Toxicology 25: 167–172, 1983

    PubMed  CAS  Google Scholar 

  • Rasmussen F. Mammary excretion of sulphonamides. Acta Pharmacologica et Toxicologica 15: 139–148, 1958

    Article  CAS  Google Scholar 

  • Rasmussen F. Mammary excretion of benzylpenicillin, erythromycin and penethamate hydroiodide. Acta Pharmacologica et Toxicologica 16: 194–200, 1959

    Article  PubMed  CAS  Google Scholar 

  • Rasmussen F. Mammary excretion of antipyrine, elhanol and urea. Acta Veterinaria Scandinavica 2: 151–156, 1961

    CAS  Google Scholar 

  • Rasmussen F. Studies on the mammary excretion and absorption of drugs. Mortensen, Copenhagen. 1966

    Google Scholar 

  • Resman BH, Blumenthal P, Jusko WJ. Breast milk distribution of theobromine chocolate. Journal of Pediatrics 91: 477–480, 1977

    Article  PubMed  CAS  Google Scholar 

  • Sargraves R, Waller ES, Goehrs HE. Tolmetin in breast milk. Drug Intelligence and Clinical Pharmacy 19: 55–56, 1985

    Google Scholar 

  • Saxena B, Shrimanker K, Gudzinskas J. Levels of contraceptive steroids in breast milk and plasma of lactaling women. Contraception 16: 605–613, 1977

    Article  PubMed  CAS  Google Scholar 

  • Schanker LS. Passage of drugs across body membranes. Pharmacological Reviews 14: 501–530, 1962

    PubMed  CAS  Google Scholar 

  • Sioufi A, Hillion D, Lumbroso P, Wainer R, Olivier-Martin M, et al. Oxprenolol placental transfer, plasma concentrations in newborns and passage into breast milk. British Journal of Clinical Pharmacology 18: 453–456, 1984

    Article  PubMed  CAS  Google Scholar 

  • Snedecor GW. Cochran WG. Statistical methods. 6th ed., pp. 150–160, University Press, Iowa, 1967a

    Google Scholar 

  • Snedecor GW. Cochran WG. Statistical methods. 6th ed., p. 392, University Press, Iowa. 1967b

    Google Scholar 

  • Somogyi A, Gugler R. Cimetidine excretion into breast milk. British Journal of Pharmacology 7: 627–628, 1979

    Article  CAS  Google Scholar 

  • Somogyi A, Gugler R. Clinical pharmacokinetics of cimetidine. Clinical Pharmacokinelics 8: 463–495, 1983

    Article  CAS  Google Scholar 

  • Stec GP, Greenberger P, Rao T, Henthorn T, Morita Y, et al. Kinetics of theophylline transfer to breast milk. Clinical Pharmacology and Therapeutics 23: 404–408, 1980

    Google Scholar 

  • Steele WH, Hawkesworth GM, Barber HE. The binding of prednisolone in human serum and to recrystallised human albumin in vitro. British Journal of Clinical Pharmacology 14: 667–672, 1982

    Article  PubMed  CAS  Google Scholar 

  • Stoeckel K, McNamara PJ, Brandt R, Plozza-Noblebrook H, Ziegler WH. Effects of concentration-dependent plasma protein binding of ceftriaxone kinetics. Clinical Pharmacology and Therapeutics 29(5): 650–657, 1981

    Article  PubMed  CAS  Google Scholar 

  • Stoehr G, Juhl R, Veals J, Symchowicz S, Gural R, et al. The excretion of rosaramicin in breast milk. Journal of Clinical Pharmacology 25: 89–94, 1985

    PubMed  CAS  Google Scholar 

  • Sudlow G, Birkett DJ, Wade DN. Further characterisation of specific drug binding sites on human serum albumin. Molecular Pharmacology 12: 1052–1061, 1976

    PubMed  CAS  Google Scholar 

  • Syversen GB, Ratkje SK. Drug distribution within human milk phases. Journal of Pharmaceutical Sciences 74: 1071–1074, 1985

    Article  PubMed  CAS  Google Scholar 

  • Townsend RJ, Benedetti TJ, Erickson SH, Cengiz C, Gillespie WR, et al. Excretion of ibuprofen into breast milk. American Journal of Obstetrics and Gynecology 149: 184–186, 1984

    PubMed  CAS  Google Scholar 

  • Tyrala EE, Dodson WE. Caffeine secretion into breast milk. Archives of Disease in Childhood 54: 787–800, 1979

    Article  PubMed  CAS  Google Scholar 

  • Valdivieso A, Valdes G. Spiro TE, Westerman RL. Minoxidil in breast milk. Annals of Internal Medicine 102: 135, 1985

    PubMed  CAS  Google Scholar 

  • Verbeeck RK, Ross SG, McKenna EA. Excretion of trazadone in breast milk. British Journal of Clinical Pharmacology 22: 367–370, 1986

    Article  PubMed  CAS  Google Scholar 

  • Von Unruh G, Froescher W, Hoffman F, Niessen M, Valproic acid in breast milk. How much is really there? Therapeutic Drug Monitoring 6: 272–276, 1984

    Article  Google Scholar 

  • Wilson JT. Drugs in breast milk. ADIS Press, Sydney, 1981

    Book  Google Scholar 

  • Wilson JT, Brown RD, Hinson JL, Dailey JW. Pharmacokinetic pitfalls in the estimation of the breast milk/plasma ratio for drugs. Annual Reviews of Pharmacology and Toxicology 25: 667–689, 1985

    Article  CAS  Google Scholar 

  • Windholz M (Ed). The Merck index. 10th ed. p. 1417, Rahway, 1983a

  • Windholz M (Ed). The Merck index. 10th ed., p. 1417, Rahway. 1983b

  • Woods PB, Robinson ML. An investigation of the comparative liposolubilities of ß-adrenoreceptor blocking agents. Journal of Pharmacy and Pharmacology 33: 172–173, 1981

    Article  PubMed  CAS  Google Scholar 

  • Yoshimura F, Nikaido H. Diffusion of ß-lactam antibiotics through the porin channels of escherichia coli K.-12. Antimicrobial Agents and Chemotherapy 27: 84–92, 1985

    Article  PubMed  CAS  Google Scholar 

  • Yurchak AM, Jusko WJ. Theophylline secretion into breast milk. Pediatrics 57: 518–520, 1976

    PubMed  CAS  Google Scholar 

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  1. Department of Clinical Pharmacology, Christchurch Hospital, Christchurch, New Zealand

    U. C. Atkinson &  Evan J. Begg

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Atkinson, U.C., Begg, E.J. Prediction of Drug Distribution into Human Milk from Physicochemical Characteristics. Clin Pharmacokinet 18, 151–167 (1990). https://doi.org/10.2165/00003088-199018020-00005

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