Changes In Drug Elimination Research Articles

Evaluation of a System-Specific Function To Describe the Pharmacokinetics of Benzylpenicillin in Term Neonates Undergoing Moderate Hypothermia.

The pharmacokinetic (PK) properties of intravenous (i.v.) benzylpenicillin in term neonates undergoing moderate hypothermia after perinatal asphyxia were evaluated, as they have been unknown until now. A system-specific modeling approach was applied, in which our recently developed covariate model describing developmental and temperature-induced changes in amoxicillin clearance (CL) in the same patient study population was incorporated into a population PK model of benzylpenicillin with a priori birthweight (BW)-based allometric scaling. Pediatric population covariate models describing the developmental changes in drug elimination may constitute system-specific information and may therefore be incorporated into PK models of drugs cleared through the same pathway. The performance of this system-specific model was compared to that of a reference model. Furthermore, Monte-Carlo simulations were performed to evaluate the optimal dose. The system-specific model performed as well as the reference model. Significant correlations were found between CL and postnatal age (PNA), gestational age (GA), body temperature (TEMP), urine output (UO; system-specific model), and multiorgan failure (reference model). For a typical patient with a GA of 40 weeks, BW of 3,000 g, PNA of 2 days (TEMP, 33.5°C), and normal UO (2 ml/kg/h), benzylpenicillin CL was 0.48 liter/h (interindividual variability [IIV] of 49%) and the volume of distribution of the central compartment was 0.62 liter/kg (IIV of 53%) in the system-specific model. Based on simulations, we advise a benzylpenicillin i.v. dose regimen of 75,000 IU/kg/day every 8 h (q8h), 150,000 IU/kg/day q8h, and 200,000 IU/kg/day q6h for patients with GAs of 36 to 37 weeks, 38 to 41 weeks, and ≥42 weeks, respectively. The system-specific model may be used for other drugs cleared through the same pathway accelerating model development.

Plasma levels of SN-38 after co-administration of gefitinib and oral irinotecan in young and old mice

2062 Background: Preclinical studies demonstrate that irinotecan, approved for I.V. administration, is most effective when administered at frequent, low doses. This administration schedule would be most practical if irinotecan were administered orally. However, the oral availability of irinotecan is limited. Gefitinib can alter the oral bioavailability of irinotecan through inhibition of gut transporters (ABCG2) that prevent intestinal absorption. Thus, we evaluated a potential method for giving irinotecan at low doses on a protracted schedule by administering orally with gefitinib. Additionally, we hypothesized that the pharmacokinetics of irinotecan may differ in older versus younger adult mice. Plasma levels of SN-38 were measured and compared in old and young Balb/c mice given oral irinotecan alone or with gefitinib. Methods: Adult (2 months old) and older, retired breeder (10 months old) Balb/c mice were orally administered irinotecan at 10 mg/kg, 20 mg/kg or 40 mg/kg either alone (control) or with 30 mg/kg PO gefitinib daily for 5 days. On the fifth day, the mice were sacrificed approximately 4–6 hours after administering drugs. Plasma was collected and SN-38 levels determined by HPLC. Results: Nearly all mice receiving irinotecan with gefitinib had a 3 fold or more increase in the level of SN-38 in the plasma as compared to the mice receiving irinotecan alone. The older mice had a more dramatic increase. Conclusions: The plasma levels of SN-38 were consistently elevated in mice treated with oral gefitinib and irinotecan when compared to mice treated with irinotecan only. The more pronounced increase in SN-38 levels seen in the older mice may be due to changes in drug elimination with aging. The results indicate that oral irinotecan can be given in the presence of gefitinib resulting in higher levels of SN-38 in the plasma of young and older mice. Combination treatment allows easier titration of irinotecan in protracted dosing protocols evaluating efficacy and toxicity in older mice, and ultimately, humans. [Table: see text] No significant financial relationships to disclose.

Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease. An update.

The effects of liver disease on pharmacokinetics and pharmacodynamics are highly variable, and difficult to predict as the mechanisms of these effects are not well understood. Since the majority of the published literature is concerned with cirrhotic liver disease, this review also focuses mainly on this area. Four different theories have been proposed to account for the effects of chronic liver disease with cirrhosis on hepatic drug elimination: the sick cell theory; the intact hepatocyte theory; the impaired drug uptake theory; and the oxygen limitation theory. While some data in support of each of the first 2 theories have been published recently, a large amount of clinical data would appear to refute both of these theories. These clinical data are substantially consistent with the latter 2 theories, which regard the decreased permeability of the capillarised sinusoid as the critical feature in cirrhosis. Further work is required to determine the applicability of each of these theories. In cirrhosis, drug glucuronidation is spared relative to oxidative drug metabolism; however, in advanced cirrhosis this pathway may also be impaired substantially. There is evidence that in cirrhosis other conjugation pathways may also be impaired to variable degrees. Growing evidence suggests that biliary drug excretion is impaired in cirrhosis. Recent studies with several racemic drugs indicate that the disease can have different effects on the hepatic elimination of individual enantiomers, which may lead to a change in the concentration-response relationships of racemic drugs in cirrhosis. A major finding which has emerged in recent years is that, even with moderate degrees of hepatic impairment, there is a decrease in clearance of drugs or active metabolites normally cleared by the kidney. The effect on renal clearance of unbound drug may be masked if there is a concomitant decrease in plasma protein binding of the drug. Neither serum creatinine levels nor creatinine clearance are useful markers of the renal dysfunction associated with cirrhosis. Both may greatly overestimate renal function in patients with cirrhosis due to increased fractional renal tubular secretion of creatinine. Altered receptor sensitivity has been observed with some drugs in cirrhosis, while for other drugs there is no change in pharmacodynamics. Precise determination of drug dosage in cirrhosis requires information on changes in pharmacodynamics and plasma protein binding in addition to changes in drug elimination. Pharmacokinetic investigations in a variety of chronic liver diseases without cirrhosis (e.g. carcinoma, schistosomiasis and viral hepatitis) suggest that in the absence of cirrhosis, impairment of drug elimination is not sufficient to warrant reduction of drug dosage. However, if cirrhosis is present, 'safe' drug use requires an awareness of the possibility of multiple interactions between changes in hepatic and renal disposition and pharmacodynamics. In chronic liver disease with cirrhosis, dosage reduction is the general rule regardless of the route of elimination of drug or metabolite.

Perfluorochemical Erythrocyte Substitutes: Disposition and Effects on Drug Distribution and Elimination

As a result of their ability to transport oxygen, PFC emulsions are being investigated for possible use in a wide variety of conditions. The recent FDA approval of F-DA to diminish myocardial ischemia during angioplasty is the first marketing approval for such a product in the world. The many potential uses of such products may result in their common application in the future, especially as new and better products are developed. The elimination, distribution, and tissue retention of PFC emulsions as well as the physiological changes that occur upon their administration have been the subject of many investigations. The results indicate that these agents may influence the pharmacokinetic properties of other drugs by a wide variety of mechanisms. Several studies have shown significant, but not necessarily consistent, changes in drug elimination and distribution following PFC emulsion infusion. Changes appear dependent on the drug examined, emulsion utilized, degree of blood exchange, species utilized, and the controls chosen for comparison. Often, the changes are time dependent indicating the importance of conducting long-term studies. While PFC emulsions do not appear to alter renal elimination of drugs, several studies have demonstrated that these agents have the potential to induce drug metabolism from several days to possibly months after exposure. Observed changes in drug volumes of distribution, which are often time dependent, may be due to changes in normal drug transport throughout the circulation and/or changes in membrane permeability and cell transport mechanisms. Changes in drug transport may result from depletion of plasma proteins or increases in alpha 1-acid glycoprotein levels due to trauma or PFC emulsion effects. The binding of drugs by PFC emulsion droplets varies greatly and PFC emulsion components displace some plasma protein bound drugs. The wide variability in the results and conclusions of the pharmacokinetic studies conducted to date emphasize the importance of utilizing adequate controls to identify which alterations are PFC emulsion specific.

Clinical pharmacokinetics of changes in drug elimination in children.

This review mainly summarizes selected aspects of the present knowledge of drug elimination kinetics independent of developmental changes, with special attention given to clinical situations. The effects of different disease states, drug interactions, changes in urinary pH, induction of microsomal enzymes, competition for renal excretory mechanisms, possible enterohepatic recirculation, binding of drugs to tissues, effects of a drug on another drug's metabolizing organ, and dose-dependent elimination, on increase or decrease of drug elimination rates in children, have been presented. Based on the available data it seems that one may postulate the following conclusions: (1) that the distribution factors as well as changes in drug elimination capacities seem to play a role, perhaps with differing relative importance, during each of the maturational periods; (2) that the physicochemical properties of a drug and its dosage, as well as changes in the volume of distribution in children, in the course of certain disease states may have a significant effect on kinetics of drug disposition in the body; (3) that systemic clearance, a model independent parameter, rather than elimination half-life, a hybrid pharmacokinetic parameter, more accurately reflects elimination of some drugs from the body; (4) that each drug and every clinical situation may require the evaluation of the direct effect on pharmacokinetic processes, since general principles may not always apply; (5) that drug disposition studies should also be performed, if possible, on patients under actual clinical situations and receiving the usual therapeutic regime, and (6) that the half-life of colistin is independent of postnatal age which should serve as a warning not to generalize about drug excretion in the young infant.