Drug Concentrations In Milk Research Articles

Subcutaneous Semaglutide during Breastfeeding: Infant Safety Regarding Drug Transfer into Human Milk.

Postpartum mothers and their healthcare providers often face the challenge of limited data regarding the safety of drug therapies during lactation. Pregnancy can lead to sustained weight gain, and obesity can negatively impact both physical and psychological well-being. The introduction of GLP-1 agonists to augment weight loss has become a topic of interest for many postpartum mothers. Our study aims to investigate the transmission of semaglutide into human milk in the first steps to ensure the safety and health of both lactating mothers and their breastfed infants. Semaglutide quantification was performed using high-resolution liquid chromatography-mass spectrometry. InfantRisk Center Human Milk biorepository released milk samples from eight women collected at 0, 12 and 24 h post-semaglutide administration. Semaglutide was extracted using protein precipitation in methanol, followed by chromatographic separation. Linear calibration curves for the method ranged between 2.5-30 ng/mL, with a limit of detection of 1.7 ng/mL and a limit of quantification of 5.7 ng/mL (LLOQ). Semaglutide was not detected in any of the collected human milk samples. A worst-case scenario of the relative infant dose (RID) was calculated using the LLOQ as the drug concentration in milk when considering semaglutide's bioavailability and long-acting dose profile. The maximum RID projected was 1.26%, far below the standard 10% safety threshold. While questions about long-term infant outcomes, the safety of maternal nutrient intake, and the nutrient content of breast milk remain, our findings suggest that semaglutide concentrations in human milk are unlikely to pose clinical concerns for breastfed infants. These results support healthcare providers in making informed decisions regarding postpartum therapeutic interventions.

Transfer of antibiotics from goat’s milk to rennet curd and whey fractions during cheese-making

The transfer of 35 antibiotics from milk to curd and whey was evaluated. Cheeses were produced at laboratory scale, from antibiotic-free goat’s milk spiked with different antibiotic concentrations between 0.25 and 4 times the Maximum Residue Limits established in milk. Drug concentrations in milk, curd and whey were analysed by UHPLC-HRMS. Results indicated that most antibiotics were mainly transferred from milk to whey (up to 85.9%), with retention percentages in the curd lower than 50%, except for ceftiofur (59.7%) and dicloxacillin (52.8%). In most cases, drug distribution was unaffected by the antibiotic concentration in milk and correlated significantly to the drug lipophilicity (Log P) for β-lactams (R2 = 0.54) and sulfonamides (R2 = 0.62). When drug ionization was considered (Log D), improved correlation coefficients were obtained for macrolides (R2 = 0.98). However, other factors besides the drug solubility should be considered to explain and predict the partitioning of antibiotics during cheese-making.

The Pattern of Blood-Milk Exchange for Antiparasitic Drugs in Dairy Ruminants.

Simple SummaryThis review article is focused on the description of the plasma–milk partition coefficients for different antiparasitic drug classes in dairy ruminants, and it contributes to rational pharmaco-therapy in lactating dairy animals, which is critical to understand the pattern of drug excretion in milk as well as the residual concentration patterns in dairy products elaborated by processing milk from drug-treated animals.The prolonged persistence of milk residual concentration of different antiparasitic drugs in lactating dairy animals should be considered before recommending their use (label or extra-label) for parasite control in dairy animals. The partition blood-to-milk ratio for different antiparasitic compounds depends on their ability to diffuse across the mammary gland epithelium. The high lipophilicity of some of the most widely used antiparasitic drugs explains their high partition into milk and the extended persistence of high residual concentrations in milk after treatment. Most of the antiparasitic drug compounds studied were shown to be stable in various milk-related industrial processes. Thus, the levels of residues detected in raw milk can be directly applicable to estimating consumer exposure and dietary intake calculations when consuming heat-processed fluid milk. However, after milk is processed to obtain milk products such as cheese, yogurt, ricotta, and butter, the residues of lipophilic antiparasitic drugs are higher than those measured in the milk used for their elaboration. This review article contributes pharmacokinetics-based information, which is useful to understand the relevance of rational drug-based parasite control in lactating dairy ruminants to avoid undesirable consequences of residual drug concentrations in milk and derived products intended for human consumption.

Prediction of drug concentrations in milk during breastfeeding, integrating predictive algorithms within a physiologically-based pharmacokinetic model.

There is a risk of exposure to drugs in neonates during the lactation period due to maternal drug intake. The ability to predict drugs of potential hazards to the neonates would be useful in a clinical setting. This work aimed to evaluate the possibility of integrating milk‐to‐plasma (M/P) ratio predictive algorithms within the physiologically‐based pharmacokinetic (PBPK) approach and to predict milk exposure for compounds with different physicochemical properties. Drug and physiological milk properties were integrated to develop a lactation PBPK model that takes into account the drug ionization, partitioning between the maternal plasma and milk matrices, and drug partitioning between the milk constituents. Infant dose calculations that take into account maternal and milk physiological variability were incorporated in the model. Predicted M/P ratio for acetaminophen, alprazolam, caffeine, and digoxin were 0.83 ± 0.01, 0.45 ± 0.05, 0.70 ± 0.04, and 0.76 ± 0.02, respectively. These ratios were within 1.26‐fold of the observed ratios. Assuming a daily milk intake of 150 ml, the predicted relative infant dose (%) for these compounds were 4.0, 6.7, 9.9, and 86, respectively, which correspond to a daily ingestion of 2.0 ± 0.5 mg, 3.7 ± 1.2 µg, 2.1 ± 1.0 mg, and 32 ± 4.0 µg by an infant of 5 kg bodyweight. Integration of the lactation model within the PBPK approach will facilitate and extend the application of PBPK models during drug development in high‐throughput screening and in different clinical settings. The model can also be used in designing lactation trials and in the risk assessment of both environmental chemicals and maternally administered drugs.

Population physiologically based modeling of pirlimycin milk concentrations in dairy cows

Predictions of drug residues in milk are critical in food protection and are a major consideration in the economics of treatment of mastitis in dairy cows. Nonlinear mixed-effects modeling (NLME) has been advocated as a suitable pharmaco-statistical method for the study of drug residues in milk. Recent developments in physiologically based pharmacokinetic (PBPK) modeling of intramammary drugs allow the combination of a mechanistic description of milk pharmacokinetics with NLME methods. The PBPK model was applied to NLME analysis of a data set consisting of milk drug concentrations from 78 healthy cows and 117 with clinical mastitis. Pirlimycin milk pharmacokinetics were adequately described by the model across the range of observed concentrations. Mastitis was characterized by increased variance in milk production volume. Udder residual volume was larger in cows with 1, or 2 or greater diseased mammary glands than in the healthy cows. Low-producing cows had a greater risk of prolonged milk residues. With the exclusion of the low-production cows, the model predicted that healthy cows required a milk discard time 12 h longer than that indicated by the label, and the diseased cows 36 h longer than indicated by the label. More pirlimycin was systemically absorbed in the gram-positive infected compared with the gram-negative infected or healthy cows, suggesting a greater risk of violative meat residues in gram-positive infected cows. Using NLME and PBPK models, we identified factors associated with changes in pirlimycin milk residues that may affect food safety. This model extends the verification of a simple physiologically based framework for the study of intramammary drugs.

Clinical lactation studies and the role of pharmacokinetic modeling and simulation in predicting drug exposures in breastfed infants.

The relative lack of information on medication use during breastfeeding is an ongoing problem for health professionals and mothers alike. Most nursing mothers are prescribed some form of medication, yet some mothers either discontinue breastfeeding or avoid medications entirely. Although regulatory authorities have proposed a framework for clinical lactation studies, data on drug passage into breastmilk are often lacking. Model-based approaches can potentially be used to estimate the passage of drugs into milk, predict exposures in breastfed infants, and identify drugs that need clinical lactation studies. When a human study is called for, measurement of the drug concentration in milk are often adequate to characterize safety. Data from these studies can be leveraged to further refine pharmacokinetic models with subsequent Monte Carlo simulations to estimate the spread of exposure values. Both clinical lactation studies and model-based approaches have some limitations and pitfalls which are discussed.

Impact of lactation on pharmacokinetics of meloxicam in goats.

Use of drug in lactating animal should be carefully considered due to its possibility of changes in pharmacokinetics as well as drug penetration in milk. The aim of this study was to assess the effect of lactation on pharmacokinetics of meloxicam after IV and IM administrations in goats. A crossover design (2×2) was used for each lactating and nonlactating group of goats with a 3-week washout period. Meloxicam (0.5mg/kg) was administered into the jugular vein and upper gluteal muscle by IV and IM routes, respectively. The plasma and milk drug concentrations were determined by high-performance liquid chromatography with diode array detector, and the pharmacokinetic analysis was carried out by noncompartmental analysis. The pharmacokinetic parameters of meloxicam in lactating and nonlactating goats were not significantly different. The IM bioavailability of meloxicam was relatively lower in lactating (75.3±18.6%) than nonlactating goats (103.8±34.7%); however, the difference was not statistically significant. Moreover, AUC ratio between milk and plasma, which represent drug milk penetration, for both IV and IM administrations was less than 1 (about 0.3). In conclusion, pharmacokinetic parameters of meloxicam are not significantly altered by lactation for either the IV or IM routes of administration and this drug does not require a different dosage regimen for lactating animals.

Physiologically based modelling of the pharmacokinetics of three beta-lactam antibiotics after intra-mammary administration in dairy cows.

Understanding the pharmacokinetics of intra-mammary antibiotics is important for the prediction of drug residues in milk and for the design of optimal dosage regimens. Unfortunately, compartmental pharmacokinetic models are not valid for this unique system. A minimal physiologically based pharmacokinetic model is presented incorporating the physiology of milk secretion, drug administration at the quarter level, drug absorption and dispersion, drug retention during the inter-milking interval and episodic drug elimination at milking. The primary objective of the study was the development and exploration of a model for major factors controlling drug concentration in milk, rather than generation of rigorously predictive pharmaco-statistical models for any particular drug. This model was implemented in a two-stage approach, using published concentration data for penicillin, cefuroxime, cephapirin and desacetyl-cephapirin in milk of healthy cows. Model simulations evaluated sensitivity and developed predictions of drug residues. The model successfully predicted both drug concentrations and drug residues in milk. The postmilking residual milk volume did not adequately explain antibiotic pharmacokinetics, requiring additional considerations for drug retention. Local sensitivity analysis indicated that increasing the number of quarters treated, the dosage, or the duration of the inter-milking interval prolonged both the persistence of drug residues and the duration that antibiotic concentration exceeded typical minimum inhibitory concentrations. The model was flexible across different beta-lactam drugs as a general description of intra-mammary pharmacokinetics. This model is suitable for the design and analysis of dosage regimens, and could be applied for the prediction of withholding periods when these antibiotic preparations are used off-label. The final model indicates that explicit consideration of the milking regimen is fundamental to the design and interpretation of pharmacokinetic studies of antibiotics in bovine milk.

Mastitis and/or plugged ducts? How to differentiate, help and treat?

Mastitis is one of the most common pyoinflammatory processes that occur in the postpartum. The mastitis incidence varies from 0.5% to 33%. Due to lack of standard algorithms, approaches to diagnosis and treatment of lactational mastitis vary between pediatricians and obstetrician-gynecologists. Plugged ducts is the basic factor that predisposes a woman to plugged milk ducts, which can lead to mastitis. Unfortunately, frequently prescribed antibacterial treatment has an adverse effect on human milk microbiota and creates subtherapeutic drug concentration in milk, which leads to antibiotic resistance in infants. Effective expression of breast milk is a key method to prevent and fight mastitis and plugged ducts. Recommendations for preferred method of breast milk expression require a personalized approach, the first of which depends on the assessment of breast nipples condition. According to some reports, 80–90% of breast-feeding women develop soreness and cracked nipples, which cause delayed or missed breastfeeding. Teaching correct breast-feeding techniques can prevent the chain of these adverse events:cracked nipples – plugged duct – lactation mastitis.Ideally, a healthy mature infant with active sucking reflex, who is breastfed effectively with a good technique, may perfectly ensure a problem-free lactation period.

Antidepressants in breast milk; comparative analysis of excretion ratios.

Despite increasing prescription rates of antidepressants in pregnant and breastfeeding women over the past decades, evidence of drug exposure for neonates through lactation is very sparse. Concentrations of three antidepressants citalopram, sertraline, and venlafaxine were measured in maternal blood and breast milk in 17 women receiving antidepressant therapy during breastfeeding period. We also computed concentration-by-dose-ratios (C/D) and milk to serum (plasma) penetration ratios (M/P). Non-parametric tests were applied. Serum concentration of citalopram and daily dosage correlated positively while daily dosage and mother milk concentration did not (rho = 0.939, p = 0.005, and rho = 0.772, p > 0.05 respectively). A significant correlation was also found between serum and milk concentrations (rho = 0.812, p = 0.05). Venlafaxine daily dosage correlated positively with the active moiety milk concentration (rho = 0.949, p = 0.014). No significant correlations were reported for sertraline. The amount of antidepressant concentrations to which neonates may be exposed, assessed as absolute infant dose (AID), was particularly low with the highest median AID being 0.16mg/kg/day for venlafaxine. No significant difference was detected for the M/P ratios between different drugs (p > 0.05), whereas the comparison of C/D ratios revealed lower values in the sertraline group, with the highest values reported for citalopram group (p = 0.007 for serum concentrations and p = 0.008 for mother milk). Findings suggest that breastfeeding under antidepressant treatment constantly exposes children with measurable drug concentrations. As daily dosage and serum concentration of the antidepressants did not predict drug concentrations in mother milk, measuring of drug concentrations in milk helps to quantify drug exposure during breastfeeding. More data-even data of drug concentrations in breastfed children-are needed to better assess the effects of drug exposure on children's development.

Eprinomectin accumulation in Rhipicephalus (Boophilus) microplus: Pharmacokinetic and efficacy assessment

Eprinomectin (EPM) is a macrocyclic lactone used against endo-ectoparasites without withdrawal time in milk and meat after its pour-on administration at 0.5mg/kg. Previous experiments evaluated the efficacy of EPM against Rhipicephalus (Boophilus) microplus in cattle. This study assessed EPM efficacy against R. (B.) microplus after topical administration at two dose rates and investigated the relationship between EPM systemic exposure in the host and drug concentrations accumulated in ticks recovered from treated animals. A standardized pharmaco-parasitological study was performed in two phases. In phase 1 eighteen Braford cattle naturally infected with R. (B.) microplus were divided into three experimental groups with a similar level of infestation (Kruskal–Wallis test, P>0.05): control group and treated groups with EPM pour-on (1 and 1.5mg/kg). Samples of heparinized blood and ticks at different life stages were taken between 0 and 21 days (d) post-administration to measure EPM concentrations by HPLC. The efficacy trial (phase 2) included eighteen Braford calves naturally infected with R. (B.) microplus divided into control group and 1mg/kg and 1.5mg/kg EPM treated groups. Female ticks (4.5–8mm) on cattle were counted between 1 and 23 days post-treatment to evaluate the efficacy of EPM. The reproductive efficiency index (REI) and the fertility efficiency index (FEI) were evaluated. Plasma concentrations of EPM showed a linear relationship with the level of dose rate administered. Peak plasma concentrations were within a range between 13.8 and 90ng/ml, which guarantee milk drug concentrations below the maximum residues level. High EPM concentrations were detected in ticks. EPM concentrations in R. (B.) microplus were correlated to plasma concentrations between 1.25 days and 21 days post-administration (r 0.84; P<0.05). EPM efficacy calculated using the Henderson–Tilton formula was 98.9% and 99.1% (7 days post-administration) and 100% (23 days post-administration) after EPM treatment at 1 and 1.5mg/kg, respectively. EPM administered at 1.5mg/kg also showed a significantly higher deleterious effect on tick fertility as measured by FEI (P<0.01). Therefore, treatment with EPM may be useful for controlling ticks in cattle, particularly in dairy production systems.

Milk and serum concentration of ceftiofur following intramammary infusion in goats.

Five dairy goats were used to determine the milk and serum concentrations along with elimination characteristics of ceftiofur following intramammary administration. One udder half of each goat was infused twice with 125mg ceftiofur with a 24-h interval between infusions. Milk samples were collected at 1, 2, 8, and 12h after the last infusion and then every 12h for a total of 7days. Blood was collected from each animal at 3, 8, 12, and 24h after infusion and then every 24h for 6days. Following a washout period of 1week, the experiment was repeated using the opposite udder half. The elimination half-life of ceftiofur from the mammary gland was 4.7h. The concentration of ceftiofur was greater than published MIC90 values for Staphylococcus spp. bacteria for 24h. Ceftiofur was absorbed into systemic circulation from the mammary gland. The maximum concentration was 552ng/mL at 3h after infusion, and the serum elimination half-life was 10h. Intramammary infusion of 125mg ceftiofur every 24h can be expected to maintain drug concentration in milk above published MIC90 for Staphylococcus spp.

Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk: a milk concentration-based prediction model.

Population pharmacokinetic (pop PK) modelling can be used for PK assessment of drugs in breast milk. However, complex mechanistic modelling of a parent and an active metabolite using both blood and milk samples is challenging. We aimed to develop a simple predictive pop PK model for milk concentration-time profiles of a parent and a metabolite, using data on fluoxetine (FX) and its active metabolite, norfluoxetine (NFX), in milk. Using a previously published data set of drug concentrations in milk from 25 women treated with FX, a pop PK model predictive of milk concentration-time profiles of FX and NFX was developed. Simulation was performed with the model to generate FX and NFX concentration-time profiles in milk of 1000 mothers. This milk concentration-based pop PK model was compared with the previously validated plasma/milk concentration-based pop PK model of FX. Milk FX and NFX concentration-time profiles were described reasonably well by a one compartment model with a FX-to-NFX conversion coefficient. Median values of the simulated relative infant dose on a weight basis (sRID: weight-adjusted daily doses of FX and NFX through breastmilk to the infant, expressed as a fraction of therapeutic FX daily dose per body weight) were 0.028 for FX and 0.029 for NFX. The FX sRID estimates were consistent with those of the plasma/milk-based pop PK model. A predictive pop PK model based on only milk concentrations can be developed for simultaneous estimation of milk concentration-time profiles of a parent (FX) and an active metabolite (NFX).

Pharmacokinetics in foremilk and antimicrobial activity of cephapirin following intramammary administration in healthy and Staphylococcus aureus-infected cows

AIM: To evaluate the kinetic profile of cephapirin and detect differences in its milk disposition following intramammary administration in healthy, and subclinically Staphylococcus aureus infected, quarters of lactating cows, to assess the minimum inhibitory concentration (MIC) of cephapirin for Staph. aureus field isolates, and to calculate the time during which drug concentrations were above the MIC (T>MIC).METHODS: Five healthy and five Staph. aureus-infected lactating cows received cephapirin at 275 mg/quarter, twice at 12-hour intervals. Foremilk samples were manually collected from individual quarters before treatments and 2, 8, 12 hours after the last drug administration, and then every 12 hours until the tenth milking. Concentrations of cephapirin and desacetyl-cephapirin were measured in milk samples after solid phase extraction and high-performance liquid chromatography analysis. A non-compartmental model was applied to data to obtain pharmacokinetic results. Eleven Staph. aureus isolates from the study-infected quarters and 30 additional isolates from cows in another two farms in the same area were used to determine MIC for cephapirin using the microdilution broth method.RESULTS: Mean maximum drug concentrations were higher in milk from healthy quarters (1334.8 (SD 1322.7) µg/mL) than in the infected ones (234.7 (SD 141.4) µg/mL), but the elimination half-life was longer in the infected (4.8 (SD 1.9) hours) than uninfected (3.3 (SD 0.33) hours) quarters (p<0.05). Mean residence time was comparable in healthy and infected quarters (approximately 8 hours). The amounts of desacetyl-cephapirin recovered in the samples were very low (below 2%). The MIC90 for all field strains of Staph. aureus (n=41) was 0.25 μg/mL. The calculated T>MIC90 was 38 (SD 13), 27 (SD 11) and 35 (SD 8) hours after last treatment in healthy, suspected and infected quarters, respectively.CONCLUSION AND CLINICAL RELEVANCE: The intramammary administration of sodium cephapirin at 275 mg/quarter, twice every 12 hours in lactating cows resulted in higher drug concentrations in milk of quarters with no infection than in the subclinically infected ones. These concentrations were above the MIC90 for 35 hours in infected cows. According to these results intramammary administration of cephapirin at 12-hour intervals during lactation should be potentially effective against Staph. aureus infection, but studies of clinical efficacy are necessary for confirmation.

Pharmacokinetics and milk secretion of gabapentin and meloxicam co‐administered orally in Holstein‐Friesian cows

Management of neuropathic pain in dairy cattle could be achieved by combination therapy of gabapentin, a GABA analog and meloxicam, an nonsteroidal anti-inflammatory drug. This study was designed to determine specifically the depletion of these drugs into milk. Six animals received meloxicam at 1 mg/kg and gabapentin at 10 mg/kg, while another group (n=6) received meloxicam at 1 mg/kg and gabapentin at 20 mg/kg. Plasma and milk drug concentrations were determined over 7 days postadministration by HPLC/MS followed by noncompartmental pharmacokinetic analyses. The mean (±SD) plasma C(max) and T(max) for meloxicam (2.89±0.48 μg/mL and 11.33±4.12 h) were not much different from gabapentin at 10 mg/kg (2.87±0.2 μg/mL and 8±0 h). The mean (±SD) milk C(max) for meloxicam (0.41±80.16 μg/mL) was comparable to gabapentin at 10 mg/kg (0.63±0.13 μg/mL and 12±6.69 h). The mean plasma and milk C(max) for gabapentin at 20 mg/kg p.o. were almost double the values at 10 mg/kg. The mean (±SD) milk to plasma ratio for meloxicam (0.14±0.04) was lower than for gabapentin (0.23±0.06). The results of this study suggest that milk from treated cows will have low drug residue concentration soon after plasma drug concentrations have fallen below effective levels.

Transfer of Parecoxib and Its Primary Active Metabolite Valdecoxib via Transitional Breastmilk Following Intravenous Parecoxib Use After Cesarean Delivery

Multimodal analgesia, including nonopioid analgesics, is usually used for several days after cesarean delivery. Because the breastfed infant receives transitional milk during this same period, it is important to know how much of a maternal analgesic drug is received by the infant. We designed this study to estimate infant exposure to parecoxib and its active metabolite valdecoxib (a cyclooxygenase-2 inhibitor) after a single IV maternal dose of parecoxib after cesarean delivery. Forty women and their infants participated in the study. Parecoxib (40 mg) was administered IV at a mean of 41 hours after birth. Milk (4 samples) and plasma (1 sample) were collected from the women over the subsequent 24 hours and drug content was measured by liquid chromatography-tandem mass spectrometry. The infants were assessed the day after parecoxib dosing. Absolute (AID) and relative infant doses (RID) of both parecoxib and valdecoxib through milk were estimated by standard methods using the naïve pooled datasets, and where possible milk/plasma (M/P) concentration ratios were calculated. Nonlinear mixed-effects modeling was also used to fit the valdecoxib milk and plasma datasets to a compartmental model and to predict M/P, AID, and RID. M/P ratios (median [interquartile range; IQR]) were 0.5 (0.15 to 1.15) for parecoxib and 0.14 (0.11 to 0.18) for valdecoxib. Using the naïve pooled datasets, AID (drug concentration in milk×daily milk intake/kg) was 0.24 (0.05 to 1.85) μg/kg/day for parecoxib, and 1.82 (1.12 to 2.73) μg/kg/day, for valdecoxib. RID was 0.04 (0.01 to 0.43) % of the weight-adjusted maternal dose (one dose in 24 hours) for parecoxib and 0.47 (0.29 to 0.69) % for valdecoxib (as parecoxib equivalents). Compartmental modeling of valdecoxib alone produced a mean (interindividual variability) M/P of 0.149 (26%), median (IQR) AID of 1.47 (0.96 to 2.03) μg/kg/day, and median (IQR) RID of 0.39 (0.28 to 0.47) %. Neonatal neurologic and adaptive capacity scores (mean=34, 95% CI 33 to 35) were consistent with a normal expected score of 35. Both the naïve pooling of data and the modeling analyses gave similar results. The RID of both parecoxib and valdecoxib was low. We conclude that a single 40 mg IV dose of the cyclooxygenase-2 inhibitor parecoxib administered to lactating women after cesarean delivery is unlikely to cause adverse effects in breastfed infants.

Modelling the concentration–time relationship in milk from cattle administered an intramammary drug

Antimicrobial drugs are often infused directly through the streak canal into the bovine udder for the treatment or prevention of mastitis. These infusions have two major problems: drug residues in milk and variable antimicrobial efficacy. Both problems are influenced by the pharmacokinetics of intramammary delivery and elimination of drugs. This pharmacokinetics does not conform to the assumptions of traditional first-order mamillary pharmacokinetic models. To help understand drug delivery into and elimination from the udder, a new approach to pharmacokinetic modelling of the udder is proposed. This new model was used to predict the movement of drug within the udder and the concentrations of drug achieved within physiological compartments of the udder. These predictions were examined using computer modelling. The model was evaluated using data from in vivo intramammary infusion of cefuroxime. The model predicts that changes in milking efficiency (residual volume), milk productivity and milking frequency can impact both the drug residue persistence and the time that milk drug concentrations exceed the minimum inhibitory concentrations for pathogens. The model provides a new tool for future evaluation of intramammary dosing studies.

Analysis and Prediction of Drug Transfer into Human Milk Taking into Consideration Secretion and Reuptake Clearances across the Mammary Epithelia

Medication use during lactation is a matter of concern due to unnecessary exposure of infants to drugs. Although some studies have predicted the extent of drug transfer into milk from physicochemical parameters, drug concentration-time profiles in milk have not been predicted or even analyzed yet. In the present study, a drug transfer model was constructed by defining secretion and reuptake clearances (CL(sec) and CL(re), respectively) between milk and plasma based on unbound drug concentrations. Through the use of this model, drug concentration-time profiles were analyzed in human milk and plasma based on data collected from the literature. CL(sec) and CL(re) values were obtained successfully for 49 drugs. Because the CL(sec) and CL(re) values were in general similar for each drug, transport across the mammary epithelia was mediated by passive diffusion in most cases. This study demonstrated that the logarithmically transformed values of CL(sec) and CL(re) can be predicted from physicochemical parameters with adjusted R(2) values of 0.705 and 0.472, respectively. Moreover, 66.7 and 77.8% of predicted CL(sec) and CL(re) values were within 3-fold error ranges of the observed values for 45 and 27 drugs, respectively. Finally, time profiles of drug concentrations in milk were simulated from physicochemical parameters. The milk-to-plasma area under the concentration-time curve ratios also were predicted successfully within 3-fold error ranges of the observed values for 71.9% of the drugs analyzed. The method described herein therefore may be useful in predicting drug concentration-time profiles in human milk for newly developed drugs.

Mammary excretion of cannabidiol in rabbits after intravenous administration.

The present study examined the distribution of cannabidiol into milk after an intravenous bolus injection (3 mg kg-1) to lactating rabbits. Drug concentrations in milk and serum were measured by HPLC. Cannabidiol was excreted into milk rapidly and the drug levels in milk increased over a 4-24-h period following the maternal injection. The mean milk to serum concentration ratio was 25.9, indicating a significant accumulation of the drug in milk.

Human Breast Milk as a Source of DNA for Amplification

Studies consistently find beneficial effects of breastfeeding on overall maternal and infant health.(1) Breast-fed infants have a significantly lower incidence of respiratory infection, otitis media, diarrhea, and dehydration, as well as fewer signs and symptoms of atopic disease.(2-4) These health advantages underscore the importance of maintaining the breastfeeding relationship for mother and infant as long as possible. Although many healthcare providers actively encourage breastfeeding for mothers and infants, there are clinical situations that require evidence-based information to inform breastfeeding management. One such situation is decision-making regarding the safety of continuing breastfeeding in the face of needed maternal medications. The current evidence regarding medication and breastfeeding utilizes measurement of drug concentrations in human milk. While strides are being made in human milk pharmacology,(5) it is important to understand the potential role of genetic variability in drug disposition and clinical response- including the impact of genetic changes on drug concentrations in human milk. By identifying genetic factors that are associated with variability in drug concentrations in human milk, we may be able to prospectively provide better guidance to breastfeeding mothers needing to take medications. As in other areas of medical science, pharmacogenetics may be able to advance the human milk science regarding medication use and breastfeeding. In order to perform pharmacogenetic studies, researchers need to obtain deoxyribonucleic acid (DNA) from a human biologic sample. Banked milk samples may help unlock some of the reasons for differences in response, toxicity, or milk drug concentrations if DNA could be extracted sufficiently from these specimens, making them useful for pharmacogenetic studies. The purpose of this study was to determine whether or not DNA could be extracted from human milk in significant amounts to be clinically useful in pharmacogenetic studies. This approach may provide an explanation for inter-patient variability of drug expression into human milk and in exposure of the recipient infant. This is a first step toward integrating pharmacogenetics into human milk pharmacology and breastfeeding management.