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Chapter 3. Determinants of drug transfer into human milk

Chapter 3. Determinants of drug transfer into human milk

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Determinants of drug transfer into human milk

FIG. 1 Passage of drug from maternal ingestion to the infant.

ingestion, the route of administration, single dosing versus steady-state dosing,

immature versus mature milk, and fore- versus hind-milk samples (1).

A pitfall in the understanding of the M/P ratio is the assumption that the milk

and plasma concentrations parallel each other throughout the maternal dosing interval. This is often true, but equally it is sometimes not true. Fig. 2(a) illustrates

the simplest case (one-compartment model) where milk and plasma concentrations

do parallel each other throughout the dosing interval. Fig. 2(b) illustrates the more

complex case where milk and plasma concentrations do not parallel each other. In

this case the milk 'compartment' is behaving as a peripheral pharmacokinetic comTABLE 2 Drug dose received by the infant via breast milk

General calculation

Dose (mg/kg/day) = Cavg• M/P • milk volume (ml/kg/day)

Worst case analysis

Dose (mg/kg/day) = Cmaxx M/P x milk volume (ml/kg/day)

where Cavgand Cmax are respective average and maximumdrug concentrations in maternal plasma at the time of

feeding; M/P is the milk to plasma ratio; milk volume is 150 ml/kg per day on average


Determinants o f drug transfer into human milk

FIG. 2 Concentration-time profile of drug in milk and plasma. (a) M/P ratio constant at all times. (b) M/P ratio

varies with time.

partment. Drugs which distribute slowly into milk will show peripheral compartment characteristics. Such drugs will accumulate in milk over time with multiple

dosing, and the M/P ratio will rise slowly. The folly of single time-point estimations of M/P ratio is self-evident.

Inaccuracy in the estimation of the M/P ratio can be avoided by the use of the

M/PAuc ratio. The M/Pauc ratio is based on the areas under the respective milk and

plasma concentration-time curves.

The AUC in plasma and milk can be calculated using the trapezoidal rule.

After single doses, the AUC from zero to infinity (AUCo_~) is calculated. The

trapezoidal rule enables the area up until the time of the last concentration measured (Clast) to be calculated, after which an extrapolation to infinity is necessary.


Determinants of drug transfer into human milk

The extrapolated area is calculated by dividing the last concentration by the slope

of the terminal part of the log-linear concentration-time curve. The larger the extrapolated area compared with the measured area, the less accurate is the overall

assessment of the AUC. Generally the extrapolated area should be <10% of the total area.

After multiple samples the AUC is calculated in plasma and milk over a dose

interval (AUCo_~). Because no extrapolation is needed such AUCs are likely to be

more accurate than those after single doses. The AUC0_~ after single doses in fact

equals the AUCo_8 at steady-state after multiple administration of the same dose,

providing the pharmacokinetics are not concentration dependent.


The dose regimen and maternal pharmacokinetics determine the maternal plasma

concentration-time profile. The shape of this profile is determined by the rate of

absorption (if the route is not i.v.), the volume of distribution (Vd), the clearance

(C1), and plasma protein binding (PB) (see Fig. 1). The net effect of all these parameters determines the unbound drug concentration in plasma. Unbound drug in

plasma equilibrates with that in milk in mammary tissue according to the physicochemical properties of the drug and the physiological properties of the plasma and

milk. The M/P ratio reflects this equilibrium.

Unfortunately the maternal pharmacokinetics are by no means constant in the

lactation period. The early postpartum period is a time of physiological turmoil for

the mother as her body adjusts from the pregnant to the postpartum state. The M/P

ratio is therefore likely to vary according to the physiological state existing at the

time of drug administration.


It is important to understand the maternal pharmacokinetics during lactation for

two reasons. Firstly, it allows the mother to be dosed appropriately for her medical

condition. Secondly, it enables the maternal plasma concentrations to be estimated,

which in turn allows the estimation of the dose received by the infant through

suckling (see Table 2).

Little is known about the kinetics of drugs during lactation. More is known about

drug disposition during late pregnancy, which is therefore a useful starting point for

discussion (Fig. 3).

Pharmacokinetics in the early postpartum period can be viewed as having characteristics similar to those of late pregnancy before settling down to the true lactational state as the effects of pregnancy wear off. This is discussed under three

headings: clearance, volume of distribution, and protein binding.


Determinants o f drug transfer into human milk








LaetAtinn vnrinhle_~

Milk composition

* pH

* protein

* fat

* diurnal variation

* fore- vs hind-milk

Suckling pattern

* frequency and duration

* volume

* duration of lactation

* breast laterality

FIG. 3 Sequence of cyclic events in the life of a woman, and variables in relation to lactation.


Clearance (CI) determines the average steady-state concentrations (Cp~) of drug in

the plasma during maintenance dosing (MD), i.e. MD - C1 x Cp~s.

The state of pregnancy is associated with increased clearance of many drugs.

Pregnancy is a hyperdynamic state in which the primary processes of drug elimination are enhanced. Clearance is related to both the rate of presentation of the drug

to the eliminating organ (mainly liver and kidney) and to the intrinsic capacity of

the organ to eliminate the drug. Drugs which are eliminated unchanged through the

kidney have increased clearance in pregnancy because of increased renal plasma

flow and glomerular filtration rate. Drugs which undergo hepatic metabolism may

have increased clearance because at least some important enzymes of the cytochrome P450 mixed function oxidase system seem to be induced (2, 3). Just how

many drugs are affected and how long these changes persist after parturition is not

known. A review of this area was provided by Nation (1980) (4).

The state of lactation provides a potential additional route for drug elimination,

via the milk itself; i.e. C|tota i - Clrena I + Clmetaboli c + Clmilk + CI...

Drug clearance in milk can occur simply by elimination of unchanged drug contained in the milk, or by metabolism within the milk. Such metabolism has been

shown for sulphonilamide which undergoes N-acetylation (5). Although there will

always be some clearance of drug via the milk through these processes, it is un51

Determinants of drug transfer into human milk

likely that the contribution of this to total drug clearance is very important. Calculations based on M/P ratios and milk volumes indicate that for most drugs the contribution of Cln~,k to Cltota, is inconsequential (6).

Maternal clearance is relevant to discussion about drug transfer into milk only

because it determines the unbound concentration of drug in maternal plasma and

therefore the amount of drug that can equilibrate with milk (see Fig. 1). The unbound concentration of drug in plasma is also considered to be the most important

component for determining drug action in the mother. The steady-state unbound

drug concentrations are likely to be the same in the non-pregnant/non-lactating

state, even though doses to achieve these concentrations might be different. Therefore, provided dosing in the mother is appropriate to achieve a given unbound

plasma concentration, the clearance can be effectively ignored and only the

unbound concentration needs to be considered in relation to drug transfer into


Volume of distribution (Vd)

During pregnancy, body water and fat are both increased and there is the extra

'compartment' of the fetus/placenta to consider. The Vd of most drugs, both

water soluble and lipid soluble, will therefore be increased, although the degree

is not great. The Vd determines the loading dose (LD) of drug to achieve a desired peak concentration (i.e. LD = Vd x Cpdesired). It is important for drugs in

which the action relates to the peak plasma concentration, e.g. paracetamol,

frusemide, or for drugs which require loading doses for early drug effect, e.g.


In lactation the Vd is also potentially larger than in the non-pregnant, nonlactating state because of the additional milk 'compartment'. The volume of distribution of the milk compartment (Vdn~lk) can be calculated using the M/P ratio and

the volume of milk (6). For most drugs the milk compartment is very small and

contributes little to the total volume of distribution (<1%) (6). It is therefore unlikely that the milk compartment has a significant influence on maternal drug concentrations. The absolute value of the Vd of a drug is important, however, in calculating the peak plasma concentration which will result after a loading dose, or during the dose interval. This concentration will influence the amount of drug in milk,

via the M/P ratio.

Protein binding (PB)

Plasma protein binding is a much abused and misunderstood pharmacokinetic parameter (7). Its importance lies only in the fact that drug concentrations, as usually

measured in body fluids, reflect both protein bound and unbound drug; i.e. plasma

concentration = unbound drug + protein bound drug (Fig. 4).


Determinants of drug transfer into human milk









Protein bound

FIG. 4

: ,,, \



Protein bound

Milk:plasmapartitioning of drug.

If it were practical routinely to measure unbound concentrations of drug, then no

discussion about protein binding would be necessary, because only unbound drug is

able to cross into breast milk (Fig. 1). Protein bound drug in plasma could then be

thought of as part of the volume of distribution of unbound drug.

Because the total drug, i.e. both protein bound and unbound is measured in conventional assays, the M/P ratio is based on the total drug concentration. Protein

binding is therefore important in our understanding of the M/P ratio.

Protein binding of many drugs is altered in pregnancy and in the early postpartum period. Acidic drugs, such as phenytoin (8), diazepam (9, 10) and salicylate

(10), which are largely bound to albumin, show the greatest change in protein

binding. This is a result of a decrease in the albumin concentration, a change in

binding affinity, and the presence of endogenous compounds which displace drugs

from protein binding sites (10). Plasma protein binding returns to normal about 57 weeks after parturition.

The importance of altered protein binding, from the maternal perspective, is that

the total drug concentration necessary for a given effect will be different. Unbound

concentrations, if measured, would not be different because these are determined

solely by unbound drug clearance.

For practical purposes, the assessment of drugs whose concentrations are measured in therapeutic drug monitoring, e.g. phenytoin, needs to take into account altered protein binding so that a realistic assessment of the unbound drug concentration can be made and dosing is appropriate, i.e. the 'normal therapeutic range' for

total phenytoin does not apply (7).

As far as the drug concentration in milk is concerned, altered protein binding

will affect the measured M/P ratio based on total plasma drug concentrations. The

M/P ratio thus measured would be expected to be different in the early, versus the

later, postpartum period.


Determinants of drug transfer into human milk


Breast physiology (see also Chapter 2)

Mammary tissue has the gross appearance of a multilobular structure composed of

alveoli and ducts (11). Macroscopic anatomy reveals multiple acini which empty

into small milk ducts (both surrounded by myoepithelial cells) from which milk is

then discharged into lactiferous ducts (11). These ducts terminate in a lactiferous

sinus which ends in the nipple for milk delivery. A licking and sucking manoeuvre

by the infant allows milk to be expressed by compression of these sinuses. Morphological changes in breast structure and alveolar organelles occur during pregnancy,

lactation and following cessation of feeding.

In the resting state the alveolus is free of secretary material and the lumen is

small. The alveolar cells are also small and contain few organelles. The lactating

alveolus has secretary material in the lumen and the cell contains abundant endoplasmic reticulum and Golgi apparatus. The cytoplasm is markedly increased relative to the nucleus at the time of parturition (12). There is increased intracellular

storage of protein and fat, and enlargement of intercellular spaces. Both synthetic

and glycolytic enzyme changes occur with lactation (13) which could impact on

milk transport or metabolism.

Hormonal regulation

Milk production is dependent on hormones. Prolactin is required for lactose formation, and oestrogens and progesterone promote duct, lobular and alveolar development. Supportive hormones for milk production include growth hormone, parathormone, thyroid hormone, insulin and cortisol (14). Insulin, hydrocortisone and

prolactin are important in cellular differentiation. Oxytocin contracts myoepithelial

cells to express milk into ducts. Oxytocin and prolactin production corresponds to

the amount of milk consumed by the infant, and the suckling vigour.

Milk composition

Milk is a suspension of fat droplets in an aqueous phase containing protein, lactose

and electrolytes. The three main constituents of breast milk which are important for

drug distribution are the aqueous itself, protein and fat (Table 3). Variations in the

concentrations of these components will be accompanied by altered M/P ratios.

Drug in the aqueous phase

Milk and plasma are separated from each other by a biological barrier through

which unbound drug passes in accordance with the principles of passive diffusion

and pH partitioning theory.


Determinants of drug transfer into human milk


Drug distribution in breast milk



D r u g dissolved


in or on


Free drug

milk lipid



Drug b o u n d to:









The mean pH of milk is lower than that of plasma, and steady-state distribution

of unbound drug between milk and plasma (Mu/Pu ratio) may be predicted by a

rearrangement of the Henderson-Hasselbalch equation (13).

For acidic drugs:

Mu / Pu -

1 + 1 0 (pHm-pKa)

1+ 10 (pKa-pHp)

For basic drugs"

Mu/Pu -

1 + 1 0 (pKa-pHm)

1 + 1 0 (pKa-pHp)

where prim and pHp are the pH of milk and plasma, respectively.

These equations predict that the Mu/Pu ratio will be <1 for acidic drugs, >1 for

basic drugs, and 1 for neutral drugs. Variations in pH during breast feeding may, in

theory, alter the Mu/Pu ratio (14). Just how important this is in clinical practice is

not known.

Drugs in lipid

Lipid is present in milk as triglycerides, cholesterol and free fatty acids, coalescing

into fat droplets. Drugs partition into milk lipid in accordance with their lipophilic

characteristics. There is a high degree of correlation (r2= 0.94) between the log

milk lipid/ultrafiltrate partition coefficient and the log of the octanol/water partition

coefficient (15). The octanol/water partition coefficient can be used to predict the

milk lipid/ultrafiltrate partition coefficient.

Drugs bound to milk protein

The total protein concentration in milk (10.3 g/l) (16) is lower than in plasma

(74.6 g/l) (17). Whey proteins account for 70-80% of milk proteins and comprise,

in order of decreasing concentrations, a-lactalbumin, lactoferrin, IgA, albumin and

lysozyme. Casein accounts for the remainder. Alpha 1 acid glycoprotein is not a


Determinants of drug transfer into human milk






Generalguidelines regarding drug transfer into milk

Highly ionised drugs tend not to concentrate in milk

Basic drugs have higher milk concentrations than acidic drugs

Drugs with high lipid solubility (high octanol/water partition coefficients) will tend to concentrate in milk

Highly protein bound drugs are less likely to achieve high concentrations in milk

significant component of milk. The protein binding of drugs in milk is less than in

plasma, and can be predicted with reasonable accuracy from the protein binding in

plasma (16). Virtually all the binding of drugs in milk is to albumin and lactoferrin


The influences outlined above are summarised in Fig. 4. It is possible to predict

M/P ratios based on the pKa of the drug, the octanol/water coefficient and the protein binding of the drug in plasma (6, 18, 19).

Total drug concentrations in milk

The sum of the amounts of drug in each of the aqueous, lipid and protein phases of

milk makes up the total amount of drug in milk.

Variations in the M/P ratio

Milk is by no means a constant medium. There is marked inter-individual variation

in milk yield, and fat and protein content (20). There is also marked intraindividual variation in the characteristics and content of the aqueous, fat and protein phases. Milk pH varies (6.8-7.7) substantially more than that of plasma, owing

to limited buffering capacity (21, 22). Fore-milk is more acidic than hind-milk.

Milk lipid content increases during the time-course of lactation from around 2.9%

in early milk (colostrum) to 5.4% in mature milk (>15 days postpartum) (23). Lipid

composition also changes during a feed, with hind-milk containing 4-5 times as much

lipid as fore-milk (24). Lipid content is also subject to diurnal variation, being higher

in the morning and reaching a nadir between 1800 h and 2200 h (25, 26). An effect of

breast laterality has also been demonstrated (27) but not confirmed (26).

The milk protein concentration is highest in colostrum, declines over 15 days

postpartum, and is relatively constant thereafter. The main changes are in the concentrations of immunoglobulins, lactoferrin and a-lactalbumin, while the albumin

concentration is relatively constant (28). Protein content also varies within a feed,

with hind milk containing around 1.5 times more protein than fore-milk.

The potential variability of M/P ratios, based on changes in pH, fat, and protein,

appears to be substantial. In practice, however, the extent of variation seems to be

minimal (29). More studies are needed on the effect of suckling patterns before

firm conclusions are reached.


Determinants of drug transfer into human milk


Maternal and mammary pharmacokinetics come together in the M/P ratio

M a t e r n a l dosing and p h a r m a c o k i n e t i c s d e t e r m i n e the u n b o u n d p l a s m a concentration of drug, w h i c h equilibrates with u n b o u n d drug in the aqueous phase of milk. In

turn, the u n b o u n d drug in milk equilibrates with milk lipids and proteins. The dose

of drug ingested by the infant depends on the total concentration of the drug in the

m i l k and the v o l u m e of milk ingested (Table 2).


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