Examples of Drugs That Appear in Breast Milk
Antithyroid uracil compounds
Nicotine ated with a low milk concentration. A highly lipid-soluble drug should accumulate in milk fat. Low-molecular-weight un-ionized water-soluble drugs will diffuse passively across the mammary epithelium and transfer into milk. There they may reside in association with one or more milk components, for example, bound to protein such as lactalbumin, dissolved within fat globules, or free in the aqueous compartment. Substances that are not electrolytes, such as ethanol, urea, and antipyrine, readily enter milk and reach approximately the same concentration as in plasma. Compounds used in agriculture also may be passed from cows to humans by this route. Finally, antibiotics such as the tetracyclines, which can function as chelating agents and bind calcium, have a higher milk than plasma concentration.
Both maternal and infant factors determine the final amount of drug present in the nursing child's body at any particular time. Variations in the daily amount of milk formed within the breast (e.g., changes in blood flow to the breast) as well as alterations in breast milk pH will affect the total amount of drug found in milk. In addition, composition of the milk will be affected by the maternal diet; for example, a high-carbohydrate diet will increase the content of saturated fatty acids in milk.
The greatest drug exposure occurs when feeding begins shortly after maternal drug dosing. Additional factors determining exposure of the infant include milk volume consumed (about 150 mL/kg/day) and milk composition at the time of feeding. Fat content is highest in the morning and then gradually decreases until about 10 p.m. A longer feed usually results in exposure of the infant to more of a fat-soluble drug, since milk fat content increases somewhat during a given nursing period.
Whether or not a drug accumulates in a nursing child is affected in part by the infant's ability to eliminate via metabolism and excretion the ingested compound. In general, the ability to oxidize and conjugate drugs is low in the neonate and does not approach full adult rates until approximately age 6. It follows, therefore, that drug accumulation should be less in an older infant who breast-feeds than in a suckling neonate.
Although abnormalities in fetal organ structure and function can result from the presence of certain drugs in breast milk, it would be quite inappropriate to deny the breast-feeding woman appropriate and necessary drug therapy. A pragmatic approach on the part of both the physician and patient is necessary. Breast-feeding should be discouraged when inherent drug toxicity is known or when adverse pharmacological actions of the drug on the infant are likely. Infant drug exposure can be minimized, however, through short intermittent maternal drug use and by drug dosing immediately after breastfeeding.
^ Study Questions
1. Concerning regulation of CYP-mediated drug metabolism, all of the following statements are true EXCEPT
(A) Drugs that competitively inhibit CYP enzymes cause a decrease in concentrations of the object (original) drug.
(B) Induction of drug-metabolizing enzymes results in a decrease in concentrations of the object (original) drug, thus potentially reducing efficacy.
(C) Induction of drug-metabolizing enzymes frequently requires the synthesis of new enzyme protein and thus may not occur immediately upon introduction of the inducing agent.
(D) Mechanism-based inactivation results in irreversible inactivation of the enzyme that lasts for the duration of the enzyme molecule.
2. Which of the following CYP enzymes is associated with metabolism of the greatest number of drugs and thus most likely to be involved in drug-drug interactions?
3. Conjugation of a drug with glucuronic acid via the glucuronosyl transferases will result in all of the following EXCEPT
(A) Production of a more water-soluble moiety that is more easily excreted
(B) A new compound that may also possess pharmacological activity
(C) A drug molecule that may be more susceptible to biliary elimination
(D) A drug molecule that may undergo enterohep-atic recirculation and reintroduction into the bloodstream
(E) A drug with a different pharmacological mechanism of action
4. Concerning the renal excretion of drugs:
(A) Drugs that are ionized in the renal tubule are more likely to undergo passive reabsorption than those that are unionized
(B) Low-molecular-weight drugs are much more likely to be actively secreted than filtered.
(C) Only drug that is not bound to plasma proteins (i.e., free drug) is filtered by the glomerulus.
(D) Decreasing renal tubular fluid pH will increase elimination of weakly acidic drugs.
5. Drug presence in breast milk is most likely for:
(A) Drugs highly bound to plasma proteins
(B) Lipid-soluble molecules
(C) Large ionized water-soluble molecules
(D) Acidic compounds
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