William L. Hayton

The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan.

The inverse relationship between serum albumin concentration and its half-life suggested to early workers that albumin would be protected from a catabolic fate by a receptor-mediated mechanism much like that proposed for IgG. We show here that albumin binds FcRn in a pH dependent fashion, that the lifespan of albumin is shortened in FcRn-deficient mice, and that the plasma albumin concentration of FcRn-deficient mice is less than half that of wild-type mice. These results affirm the hypothesis that the major histocompatibility complex–related Fc receptor protects albumin from degradation just as it does IgG, prolonging the half-lives of both.

Pharmacokinetic modeling in aquatic animals I. Models and concepts

Abstract While clinical and toxicological applications of pharmacokinetics have continued to evolve both conceptually and experimentally, pharmacokinetic modeling in aquatic animals has not progressed accordingly. In this paper we present methods and concepts of pharmacokinetic modeling in aquatic animals using multicompartmental, clearance-based, non-compartmental and physiologically-based pharmacokinetic models. These models should be considered as alternatives to traditional approaches, which assume that the animal acts as a single homogeneous compartment based on apparent monoexponential elimination. Multicompartmental models are a necessary increase in complexity when elimination is biphasic or when there is a widely different distribution between high perfusion and low perfusion tissues. Alternatives to traditional rate-constant based models are clearance-based compartmental models, which have parameters that may be interpreted in terms of the controlling physiological and biochemical processes. Non-compartmental methods characterize uptake, distribution, elimination, and persistence without making assumptions about the underlying model topology. Development of physiologically-based models is highly desirable because they allow extrapolation to other species, body sizes and environmental conditions.

Maturation and growth of renal function: Dosing renally cleared drugs in children

A model was developed that characterized the maturation and growth of the renal function parameters (RFPs) glomerular filtration rate (GF), active tubular secretion (AS), and renal plasma flow (QR). Published RFP values were obtained from 63 healthy children between the ages of 2 days and 12 years. Maturation over time was assumed to be exponential from an immature (RFPim) to a mature (RFPma) level; for growth, RFPim and RFPma were assumed to follow the allometric equation: RFP(age, W)=aWbe−kmat *age+cWb(1−e−kmat *age), where W is body weight, kmat is the maturation rate constant, b is the body weight exponent, and a and c are RFPim and RFPma at unit W. The model-based equation was fitted to the age-W, RFP values by a nonlinear least-squares method. For GF, the maturation half-life was 7.9 months (90% maturation, 26 months), the body weight exponent was 0.662, and the ratio c/a (which reflected the magnitude of the maturation influence) was 3.1. For AS and QR, the maturation half-lives were about 3.8 months and the ratio c/a was about 1.8. For renally eliminated drugs, the model can be used to estimate dosing regimens that are based on the adult dosing regimen and the age and weight of the child.

Allometric scaling of xenobiotic clearance: Uncertainty versus universality

Statistical analysis and Monte Carlo simulation were used to characterize uncertainty in the allometric exponent (b) of xenobiotic clearance (CL). CL values for 115 xenobiotics were from published studies in which at least 3 species were used for the purpose of interspecies comparison of pharmacokinetics. The b value for each xenobiotic was calculated along with its confidence interval (CI). For 24 xenobiotics (21%), there was no correlation between log CL and log body weight. For the other 91 cases, the mean±standard deviation of the b values was 0.74±0.16; range: 0.29 to 1.2. Most (81%) of these individual b values did not differ from either 0.67 or 0.75 at P=0.05. When CL values for the subset of 91 substances were normalized to a common body weight coefficient (a), the b value for the 460 adjusted CL values was 0.74; the 99% CI was 0.71 to 0.76, which excluded 0.67. Monte Carlo simulation indicated that the wide range of observed b values could have resulted from random variability in CL values determined in a limited number of species, even though the underlying b value was 0.75. From the normalized CL values, 4 xenobiotic subgroups were examined: those that were (i) protein, and those that were (ii) eliminated mainly by renal excretion, (iii) by metabolism, or (iv) by renal excretion and metabolism combined. All subgroups except (ii) showed a b value not different from 0.75. The b value for the renal excretion subgroup (21 xenobiotics, 105 CL values) was 0.65, which differed from 0.75 but not from 0.67.

Pharmacokinetics of ketamine and two metabolites in the dog

The plasma concentrations of ketamine, N-demethylketamine (I), and the cyclohexene metabolite (II) formed by oxidation of I were determined at various times after rapid i.v. administration of 15 mg of ketamine HCl/kg of body weight to dogs. A pharmacokinetic model that included two compartments for ketamine and one compartment for each metabolite was developed. Ketamine distributed rapidly with (t1/2α averaging 1.95 min. The apparent volumes of the central and peripheral compartments for ketamine averaged 542 and 1940 ml/kg of body weight, respectively, and the (t1/2)β averaged 61 min. The model indicated that 62% of ketamine was transformed to I and that 11% of I was converted to II. The apparent volumes of distribution of I and II averaged 61% and 59% of body weight, respectively. The total body clearances (plasma) of ketamine, I, and II averaged 32.2, 89.4, and 8.54 ml/min/kg, respectively. Plasma protein binding was determined by equilibrium dialysis; it averaged 53.5% for ketamine (concentration range 0.34– 19.5 μg/ml), 60.3% for I (0.05– 19.6 μg/ml), and 70.1% for II (0.09– 0.58 μg/ml). A minimum anesthetic concentration of 3 μg ketamine HCl/ml plasma was used with the model to predict that the duration of ketamine anesthesia after an i.m. dose would not be significantly affected if the absorption t1/2varied from 0.48 to 31 min. The model also predicted that accumulation of I and II would not interfere with ketamine anesthesia that was prolonged by repeated doses, each dose administered i.v. on termination of anesthesia from the previous dose.

FcRn in the Yolk Sac Endoderm of Mouse Is Required for IgG Transport to Fetus

In adults, the nonclassical MHC class I molecule, FcRn, binds both IgG and albumin and rescues both from a degradative fate, endowing both proteins with high plasma concentrations. FcRn also transports IgG from mother to young during gestation. Anticipating that a detailed understanding of gestational IgG transport in the mouse may give us a useful model to understand FcRn function in the human placenta, we have studied FcRn in the mouse yolk sac placenta in detail. Analyzing day 19–20 fetuses of the three FcRn genotypes resulting from matings of FcRn+/− parents, we found that FcRn−/− fetuses showed negligible IgG concentrations (1.5 μg/ml), whereas IgG concentrations in FcRn+/− fetuses were about a half (176 μg/ml) that of FcRn+/+ fetuses (336 μg/ml), indicating that FcRn is responsible for virtually all IgG transport from mother to fetus. Immunofluorescence and immunoblotting studies indicated that FcRn is expressed in the endoderm of the yolk sac placenta but not in other cells of the yolk sac placenta or in the chorioallantoic placenta. IgG was found in the endoderm of both FcRn+/+ and FcRn−/− yolk sac placentas and in the mesenchyme of FcRn+/+ but was missing from the mesenchyme of FcRn−/− yolk sac placentas, indicating that IgG enters the endoderm constitutively but is moved out of the endoderm by FcRn. The similarities of these results to human placental FcRn expression and function are striking.

Presystemic branchial metabolism limits di-2-ethylhexyl phthalate accumulation in fish

Despite the high lipophilicity of di-2-ethylhexyl phthalate (DEHP), fish do not extensively accumulate this ubiquitous environmental contaminant. Experiments with rainbow trout (Salmo gairdneri) fitted with an indwelling cannula showed that the majority of [14C]DEHP did not reach the systemic circulation of the fish, but was present in the exposure water as metabolites. Pharmacokinetic analysis, using a compartmental model that included the gill as a separate metabolic compartment, indicated that DEHP was extensively metabolized as it diffused from water to blood. Isolated perfused gill arches of trout metabolized DEHP in the exposure bath to monoethylhexyl phthalate, demonstrating the ability of the gill to prevent DEHP entry into the fish. The relationship between metabolic clearance and tissue perfusion further suggests that metabolism in the gill can play an important role in determining the accumulation and toxicity of organic chemical pollutants in fish.

Rate-limiting barriers to intestinal drug absorption: A review

The intestinal epithelium is composed of several structures that could serve as barriers to the transfer of drugs from the GI lumen to the systemic circulation. An aqueous stagnant layer that overlies the apical membrane and the subepithelial blood flow are potential barriers to the absorption of drugs that readily penetrate the absorbing cell of the epithelium. The apical, basal, and basement membranes are potential barriers to the absorption of less permeable drugs. The cytoplasm of the absorbing cell is a relatively thick barrier that must also be traversed. While the location and structure of these potential barriers are well known, those barriers that are operative and the kinds of molecules for which they are operative are not known. The structure and permeability properties of the potential barriers are considered, along with the roles of the paracellular pathway and countercurrent exchange in the villus circulation.

Age-associated changes in ceftriaxone pharmacokinetics.

SummaryCeftriaxone pharmacokinetic parameters were compiled from recent publications. The subjects (27 female, 93 male) were from 1 day to 92 years old and appeared to have normal renal and hepatic function. In 1- to 8-day-old neonates, the half-life averaged 19 hours; it declined to 6.3 hours in 1- to 6-year-old subjects and then increased gradually throughout the remainder of the life-span to 14 hours in 75- to 92-year-old subjects. The age-associated changes in half-life appeared to result from changes in systemic clearance. The fraction of the dose eliminated renally averaged 70% in neonates and declined throughout childhood to 40 to 60% in adults, in whom it was age invariant. No clinically significant differences between males and females were detected in ceftriaxone kinetic parameter values. Plasma protein binding of ceftriaxone (100 mg/L) was about 70% in neonates and it increased throughout childhood to the adult value of 90 to 95%. To achieve a given free concentration of ceftriaxone, the same dosage per unit surface area can be used for children and adults, provided glomerular filtration and biliary secretion function are normal for age. Dosage should be reduced by as much as a factor of 5 in neonates less than 1 week of age and perhaps by a factor of 2 in the very old.

Estimation of Creatinine Clearance from Serum Creatinine Concentration — A Review

FOR PATIENTS WITH RENAL IMPAIRMENT, creatinine clearance (Ccr) may be used to adjust the dosage regimen of drugs excreted partially or completely by the kidney. However, accurate measurement of Ccr is inconvenient and is not routinely done for dosage regimen adjustment. Furthermore, the time that is required for Ccr determination is too long to permit the use of measured Ccr values for immediate dosage regimen design. A number of methods have been proposed for the estimation of Ccr from the concentration of creatinine in blood serum (Scr). Measurement of Scr is made relatively quickly; it may be available from an SMA 12/60 or other multiple analysis instrument profile. Thus, the use of Ccr estimated from Scr is a clinically attractive approach for the adjustment of dosage regimens for renally impaired patients. In addition, it is possible to monitor Scr and adjust dosage promptly in response to changes in renal function. This paper reviews the pharmacokinetics of creatinine and several methods for the estimation of Ccr from Scr. The limitations and advantages of each method are discussed and the use of Ccr for adjustment of dosage regimen for patients with impaired renal function is considered.