R. Don Brown

Drug Excretion in Human Breast Milk

SummaryThe excretion of drugs in human breast milk is reviewed with regard to milk production, composition, feeding patterns and mechanisms of drug transfer into milk. Fundamental principles of breast milk excretion are used to construct a pharmacokinetic approach useful for the study of most drugs. An infant-modulated 3-compartment open model is proposed for drug distribution and elimination in the breast feeding woman. Milk/plasma drug concentration ratios are projected on the basis of pH partitioning. While some studies confirm these projections, other studies demonstrate a need to consider additional factors such as lipid solubility and protein binding characteristics of a drug in milk.Data are lacking for most drugs and hence dosing via milk or risk to the infant remains speculative. Very few pharmacokinetic studies of both milk and infant plasma were found. A review of selected drug classes cites available information as a basis for future studies. Few drugs are contraindicated in breast feeding women, but supportive data for either proscriptions or permissive statements are often lacking. A neglected but potentially serious infant risk — impaired behaviour and development — is discussed from the standpoint of emerging animal data.Conceptually valid and comprehensive studies on drug excretion in breast milk are needed if this valuable nutrient for infants is to be made available safely.

Single-dose pharmacokinetics of ibuprofen and acetaminophen in febrile children

The disposition of antipyretic drugs is central to the understanding of their action in children. Accordingly, the authors measured plasma levels of acetaminophen and ibuprofen in 153 febrile children for 6 hours after a single dose of either acetaminophen (12.5 mg/kg) or ibuprofen (5 or 10 mg/kg). Cmax occurred about 2 1/2 hours before maximum antipyresis, when plasma acetaminophen or ibuprofen was 25 to 50% less than Cmax. Most plasma level data fit a one‐compartment open model, and this suggests a pharmacodynamic basis for the observed lag between Cmax and maximum antipyretic response. Plasma levels (and AUC0→∞) of ibuprofen 10 mg/kg were less than expected for a two‐fold increase in dose. For acetaminophen, the tlog was less than ibuprofen, Ka was more than ibuprofen, and β was less than ibuprofen. The ibuprofen β was not dose dependent, but the Vd was dose and model dependent. In contrast, ibuprofen Clp was dose and model independent. Acetaminophen pharmacokinetics were similar to those previously reported. Initial temperature, race, gender, prior medications, or diagnosis did not confound the results for ibuprofen or acetaminophen. Accordingly, a pharmacodynamic basis is a more likely explanation for the initial temperature effects found previously for antipyretic drugs in children. Ibuprofen (5 and 10 mg/kg) AUC0→∞ was higher in the older (≥ 2.5 yrs) children and the Vd and Clp were lower in the older children, when discriminated by age or pharmacokinetic parameters. The observed dose dependency of AUC0→∞ and the effect of age on ibuprofen disposition must be considered if pharmacokinetic interpretations are used to develop the antipyretic dose of ibuprofen in children.

Integrated Pharmacokinetic–Pharmacodynamic Model for Acetaminophen, Ibuprofen, and Placebo Antipyresis in Children

A descriptive profile for antipyretic drug action has been documented for children. However, a linked pharmacokinetic–pharmacodynamic (PK/PD) model is central to the understanding of antipyretic drug action in febrile children. This was examined for previously reported data from 178 febrile children who received a single oral dose of acetaminophen (APAP) (12.5 mg/kg), ibuprofen (IBU) (5 or 10 mg/kg), or placebo. Rectal temperatures and plasma levels (μg/ml) of APAP and IBU were measured for up to 12 hr after drug administration. Nonlinear regression analyses were applied to these measurements and yielded simultaneous solutions of an integrated one-compartment PK, link, and SigmoidEmaxeffect model in 102/153 febrile children given APAP or IBU. The PK parameters (tlag,ka, β,T1/2β,AUC0–∞,Vd/F,andClp/F) were not different than those reported previously, except the APAPkawas significantly lower. The link component yieldedkeos of 0.58±0.06 (X±SE), 0.70±0.11 and 0.57 ± 0.11 hr-1for APAP, IBU05, and IBU10, respectively: the SigmoidEmaxcomponent yieldedEC50s (μg/ml) and sigmoidicity (γ) of 4.63±0.39 and 3.98±0.42 for APAP, 11.33±1.35 and 3.97±0.58 for IBU05 and 12.83±1.89 and 4.27±0.63 for IBU10. On visual inspection of the efficacy–time profiles of the febrile children, a number of them had an apparent linear function (slope; Δ°C/hr) and/or a sinusoidal cyclic function “confounding” standard approaches to PD analysis. Thus, the temperature profiles of 91/102 children given APAP or IBU required the addition of a slope (Δ°C/hr) and/or a sinusoidal cyclic function to the SigmoidEmaxcomponent to fit the data satisfactorily. All 22 children given a placebo also required a slope and/or a cyclic function in their PD model. The residual Δ°Cs (observed-predicted) of the placebo group were not significantly different from 0. Thus, no placebo antipyretic effect was observed. Dose dependency of IBUAUC0–∞was confirmed; doubling the dose from 5 to 10 mg/kg increased theAUC0→∞by only 1.5-fold. The confounding effect of initial temperature (Tempi) on antipyretic efficacy in all treatment groups except placebo was also confirmed to expose nonlinear pharmacodynamics. A significant (p=0.03) contribution ofTempi(but not age) on the value of the slope function was found. There was no consistent effect of age orTempi, on the cyclic component of the integrated model of antipyresis. In addition, a multiple linear relationship of age andTempiwas observed with a large number of the PK, link, and PD variables in those who received IBU. Dose, age, andTempiinteracted with β in a significant multiple linear relationship withAUC0–∞. The effects of IBU dose, age, andTempiare pervasive and cascade down the chain of events leading to the PD response. The etiology of pyresis may create the slope function, the magnitude of which may be partially due to the underlying disease. In some cases, the cyclic function may be explained by temperature regulation. Regardless of their cause, both confound analysis of drug action and make the simple, unmodified SigmoidEMaxeffect model less than satisfactory for interpretation of antipyretic drug effects. The influence of Tempion the magnitude of antipyretic drug response is also a finding with major impact on PD investigations of antipyretic medications. In children receiving IBU, dose and age are also confounders, in addition toTempi. A multiplicity of covariables must be taken into account when developing appropriate dosing regimens for these antipyretics in febrile children.

Cochlear Morphology of the Audiogenic-Seizure Susceptible (Ags) Or Genetically Epilepsy Prone Rat (Gepr)

The organ of Corti (OC) of the genetically epilepsy prone rat (GEPR), a strain which is highly susceptible to audiogenic seizures (AGS), was examined by means of the scanning electron microscope (SEM). Ten female GEPRs (seizure intensity score of 2 or 3) and 10 female control rats (seizure intensity score of 0) were used in this study. (Seizure intensity was scored on an ascending scale of 0-9; 0 being no seizure (Jobe et al., 1973).) Each rat was perfused with buffered glutaraldehyde and the temporal bones fixed for one week in formalin. After decalcification, staining and microdissection, the entire OC was prepared for scanning electron microscopy (SEM). The GEPR organ of Corti contained several morphological differences when compared with controls. 1) In all 10 GEPRs, the headplates forming the top of the tunnel of Corti exhibited some form of structural abnormality. 2) Five animals had some form of stereocilia aberration of the inner (IHC) and/or outer (OHC) hair cells. 3) In 4 animals, significant numbers (10-15%) of IHCs were missing in large segments of all cochlear turns. 4) In 2 GEPRs, all OHCs were absent from the middle turn to the hook. In these 2 animals, IHCs were present in the upper middle turn but became less numerous and completely absent in the basal turn and hook. 5) One set of cochleas had 1000 more OHCs than had those of control rats. Since GEPRs are genetically susceptible to seizures, the preceding cochlear abnormalities are probably genetically-induced developmental defects. It is likely that the abnormally long stereocilia, mis-shaped stereocilia and deficits in hair cell populations are a consequence of the distorted headplates. The elongated stereocilia could be a compensatory attempt to contact the tectorial membrane during development. The mis-shaped stereocilia and hair cell deficits could represent a failure of compensatory mechanisms. The cochlear abnormalities may play a role in both susceptibility and intensity of audiogenic seizures.

Antimicrobial Therapy in Neonates, Infants and Children

SummaryMany antimicrobial medications may be administered to paediatric patients with a degree of impunity because they are relatively non-toxic and have a wide therapeutic margin. However, because of different pharmacokinetics from those in adults, the potential for toxicity exists with the use of some of these agents. Drug absorption in paediatric patients, either orally or parenterally, is generally similar to that in adults, except among neonates and, particularly, premature neonates. Similarly, in neonates, drug distribution is altered, plasma protein binding is decreased and hepatic metabolism and renal excretory capacity are limited by physiological immaturity. Thus, in neonates, only drugs that have pharmacokinetically derived dosage schedules should be used, and therapeutic monitoring of plasma drug concentrations is recommended during therapy with aminoglycosides, vancomycin and chloramphenicol. In older infants and children, the pharmacokinetics of antimicrobial drugs generally approximate those in adults, and recommended dosages have been determined relative to bodyweight. Therapeutic monitoring of plasma drug concentrations may be important in certain patients, such as those with major organ failure, and may be useful in cases of suspected noncompliance. Additional pharmacokinetic considerations concerning antimicrobial medication and paediatric patients are the extent to which drug therapy penetrates the cerebrospinal fluid in meningitis, and the potential for and implications of exposure of infants to antimicrobial medications excreted in breast milk.

Effects of intra-arterially and intravenously administered ethacrynic acid and furosemide on cochlear N1 in cats☆

Abstract Cats were prepared to record from the cochlear round window. Various doses of sodium ethacrynate and furosemide were administered intraarterially (ia) and iv to ascertain their effect on cochlear N 1 . Equivalent doses of sodium ethacrynate by the ia and iv routes of administration are the same (about 3.5 mg/kg). This, coupled with the finding of a definite latent period after administration of sodium ethacrynate by either route, indicates that ethacrynic acid may be exerting its ototoxic effect through the action of a metabolite. By contrast, the equivalent doses of furosemide by the 2 routes are different (the ia dose being smaller, as expected), and there is no latent period after its administration, indicating a direct action on the cochlea.

Effect of bumetanide on the positive endocochlear dc potential of the cat

Abstract Twenty-seven cats were recorded from the scala media of the cochlea in order to evaluate the reduction in the positive endocochlear dc potential (EP) produced by iv bumetanide and to compare these changes to the bumetanide-induced N1 depression observed previously. A linear relationship does exist between the dose of bumetanide administered and the resultant mV reduction of the EP. The equation for the regression line of this dose-response to bumetanide is y (maximal reduction of EP) = 259.5 + 92.8 × (log mmol/kg iv bumetanide). The maximal reduction of EP occurring within 1 min after the larger doses of bumetanide correlates well with changes in N1 previously observed after similar doses. When multiple linear regression analysis is performed, the amount of N1 depression produced by a particular dose of bumetanide is found to be linearly related to the amount of EP reduction produced by that dose of bumetanide. These data indicate that the acute ototoxicity produced by this “loop” diuretic is due to its effect on EP.

Comparison of the cochlear toxicity of sodium ethacrynate, furosemide, and the cysteine adduct of sodium ethacrynate in cats☆☆☆

Ninety-one cats were recorded from the cochlear round window in order to evaluate the degree of N1 depression produced by iv sodium ethacrynate (NaEA), furosemide (FUR), and the cysteine adduct of NaEA (NaCEA). The dose-response curves for NaEA, FUR, and NaCEA are parallel, NaCEA being more potent than NaEA, and NaEA more potent than FUR. Their dose vs time to maximal effect curves are also parallel, except that there is an irreducible latent period after NaEA. The cysteine adduct of sodium ethacrynate is more potent than FUR in this relationship, and FUR more potent than NaEA. Thus, NaEA, FUR, and NaCEA appear to produce ototoxicity by acting on the same cochlear site and by way of the same mechanism of action. The durations of the N1 depression produced by NaEA and NaCEA are much longer than that produced by FUR. These differences, however, are probably due to NaEA and NaCEA not diffusing out of the cochlea as readily as FUR, or to FUR being inactivated in some way by tissue in the cochlea. In addition, NaEA may be converted, in part if not wholly, to NaCEA before exerting an ototoxic effect. Finally, the data support the clinical observations that ethacrynic acid is more liable to produce ototoxicity than furosemide. This is probably due to the greater ototoxic potency of ethacrynic acid and its much longer duration of ototoxic action.

Comparative Acute Cochlear Toxicity of Intravenous Bumetanide and Furosemide in the Purebred Beagle

Abstract: Comparisons were made of the effects of various doses of intravenous bumetanide and furosemide on the primary auditory afferent activity (N1) and cochlear microphonics (CM) of beagles. The dose‐response relationships of the N1 depressions to bumetanide and furosemide are parallel; those of the CM depressions are also parallel but have a much shallower slope than those of the N1 depressions. With both drugs, N1 depression occurs at lower doses than does CM depression. The N1 depression produced by a particular dose of bumetanide or furosemide bore a linear relationship to the CM depression produced. This finding supports the postulate that the cochlear site and mechanism of ototoxic action of the loop diuretics are directed at an earlier step of the cochlear transduction process than N1. Using N1 depression as the gross electrophysiologic index of ototoxicity, the acute ototoxic potency of bumetanide in beagles is approximately 6.5 times that of furosemide, whereas its diuretic potency is 40 to 60 times that of furosemide. Therefore, when clinical dosages of the two drugs are considered, the relative acute ototoxic potency of bumetanide in the beagle is 0.11 to 0.16 that of furosemide. This range is identical to the relative ototoxic potency of 0.11 to 0.16 previously obtained in the cat. Serum concentrations of bumetanide and furosemide increased linearly with the doses of the two drugs, except for the highest dose given (100 mg/kg for both drugs). The serum concentrations at that dose of both drugs are less than the mathematically predicted values. Histologic (light‐microscopic) examination of the cochleas did not reveal any significant pathology.

Flurbiprofen in Post‐Partum Women: Plasma and Breast Milk Disposition

The plasma and milk disposition of flurbiprofen (FB) was assessed in healthy women during the early post‐partum period after multiple doses of FB. The results confirmed that a pragmatic study design is an attainable requirement for definitive statements about the excretion of FB in transitional milk. Nine doses of FB (50 mg per dose) were administered during three days. Paired milk and plasma samples were obtained during this period of dosing as well as after the last dose. The plasma data were used to derive an equation, which was then used to simulate cumulative plasma profiles for multiple doses given at unequal time intervals. The observed data corresponded to the simulated cumulative profiles of FB in plasma. The plasma elimination half‐life of FB during early lactation was slightly prolonged (mean 4.8 hrs) as compared to reported values for normal adult men. The peak plasma concentrations of FB were comparable to those reported for healthy volunteers. In 10 of 12 women (3–5 days post‐partum) the FB concentration in breast milk was less than 0.050 μg/ml. In two women the milk concentrations of FB were 0.06, 0.07 and 0.07 μg/ml as found in only three samples. We conclude that, on the basis of dose found in milk, FB is safe for women breast feeding their infants in the early post‐partum period.