Gordon L. Coppoc

Species dependent gentamicin pharmacokinetics and nephrotoxicity in the young horse

Gentamicin pharmacokinetics and nephrotoxic potential were evaluated in twelve 2 to 3 month-old horses. Whereas recent evidence in our clinic indicated that young horses may be especially susceptible to gentamicin nephrotoxicity, young rabbits and rats are usually resistant. Gentamicin (4.5 mg/kg) was given by rapid intravenous injection. Serum gentamicin concentrations over a 13-hour period were fitted to an open, two-compartment, pharmacokinetic model. Subsequently, the same horses were divided into groups of 3 horses each. Each group received 0, 2.2, 4.4 or 8.8 mg gentamicin/kg, intramuscularly, every 12 hours for 15 days. Renal function was monitored. Peak and trough gentamicin concentrations were monitored daily. Renal sections were collected for histopathologic and electron microscopic examination. The (mean +/- SD) serum halflife was 194 +/- 37 minutes, total body clearance (ClB) was 1.65 +/- 0.79 mL/min/kg and volume of distribution at steady state (Vd(ss)) was 30.6 +/- 9.4 L/100 kg. Decreased renal function, as detected by elevated serum urea nitrogen or creatinine concentrations, was detected only in the two youngest foals (including animals in both the 4.4 and 8.8 mg/kg dose groups). The trough serum gentamicin concentrations of these 2 horses increased over time. These horses had the lowest ClB and Vd(ss) in the intravenous study. Morphologic changes were seen in kidneys of all treated horses and were similar to those occurring with gentamicin toxicity in other species. Our results support the clinical impression that very young horses may be more susceptible than adult horses, and adults of other species, to gentamicin nephrotoxicity.

Plasma and cerebrospinal fluid pharmacokinetics of cytosine arabinoside in dogs

SummaryCytosine arabinoside (ara-C) is a component of many protocols for the treatment of CNS (central nervous system) leukemia and lymphoma in humans and dogs. It is also used for the prophylaxis of CNS metastasis in acute lymphoblastic leukemia. Although ara-C enters the cerebrospinal fluid (CSF) of human cancer patients after i.v. administration, it is unclear whether a similar CNS distribution occurs in humans whose blood-brain barrier has not been compromised by invasive disease. No information on the penetration of ara-C into the CSF in dogs is available. We studied the plasma and CSF pharmacokinetics of 600 mg/m2 ara-C in ten healthy male dogs after its administration as a rapid i.v. bolus (six dogs) or as a 12-h i.v. infusion (four dogs). Ara-C concentration in blood and CSF samples was determined by high-performance liquid chromatography (HPLC). After an i.v. bolus of ara-C, the mean plasma distribution half-life was 7.1±4.5 min and the mean elimination half-life was 69±28 min. The mean plasma clearance was 227±125 ml min−1 m−2. The peak concentration of ara-C in the CSF was 29±11 μm, which occurred at 57±13 min after the ara-C bolus. The CSF elimination half-life was 113±26 min. During a 12-h infusion of ara-C (50 mg m−2 h−1), the plasma steady-state concentration was 14.1±4.2 μm, the CSF steady-state concentration was 8.3±1.1 μm, and the CSF: plasma ratio was 0.62±0.14. The plasma eleimination half-life was 64±19 min and the plasma clearance was 214±69 ml min−1 m−2. The CSF elimination half-life was 165±28 min. No clinically significant toxicity was observed over a 21-day period following drug administration in either of the treatment groups. Our data indicate that ara-C crosses the blood-brain barrier in normal dogs and that i.v. administration of this drug has potential as a treatment modality for neoplasia involving the CNS.

Pharmacokinetics and comparative nephrotoxicity of fixed-dose versus fixed-interval reduction of gentamicin dosage in subtotal nephrectomized dogs

There is presently no consensus as to the relative safety of fixed-interval/reduced dose (FI) vs fixed-dose/increased interval (FD) dosage adjustment regimens for use in renal insufficiency. This study compared their nephrotoxic potential using gentamicin in beagle dogs with renal insufficiency secondary to subtotal surgical nephrectomy. Pharmacokinetic analysis in six dogs showed that this surgical procedure resulted in a decreased total body clearance of drug and a marginally contracted volume of the central compartment. An allometric analysis of gentamicin disposition in different species was used to derive a human-equivalent maximum canine nontoxic dose of 9 mg kg-1 day-1. Nephrotoxicity was detected by histopathologic analysis and changes in the pre- and post-drug treatment, creatinine clearance, and daily drug elimination rate constants. This allometric dose did not produce clinical toxicity in a control group of six dogs with intact kidneys given drug for 14 days. Dosage adjustments within the FI and FD groups were based on serum creatinine concentrations 10 days after surgery. Statistical analysis of morphological and functional parameters indicated that the FD method was significantly less toxic than the FI regimen.

Gentamicin pharmacokinetic changes in induced acute canine nephrotoxic glomerulonephritis.

Most clinical schemes used to adjust gentamicin dosage regimens in renal insufficiency assume that the volume of distribution remains constant. The purpose of this investigation was to determine the pharmacokinetic parameters of gentamicin (two-compartment open model) before and at two points during the acute phase of experimentally induced nephrotoxic (injection of anti-glomerular basement membrane antibody) glomerulonephritis in beagle dogs. Disease was verified by decreased 24-h creatinine clearance, increased 24-h urinary protein excretion, and characteristic immunofluorescent, light- and electron-microscopic lesions. After disease induction, the concentration of drug in serum at time zero (Cp0) was significantly decreased and the volume of the central compartment (Vc) and the volume of distribution (Vd(area)) were increased in all treated dogs. These findings suggest that the assumption of unchanged volume of distribution in acute glomerulonephritis could lead to a serious overestimation of serum drug concentration.

Single Dose Gentamicin Nephrotoxicity in the Dog: Early Functional and Ultrastructural Changes

A single dose (15mg/kg) of the aminoglycoside antibiotic gentamicin was administered intravenously to 4 purebred 5-month old beagles. Six 24-hour creatinine, urea, phosphate, sodium, and potassium clearances were performed, three before and three after gentamicin infusions, as were hematology and urinalysis. Animals were necropsied on the fourth day after drug infusion. Renal clearances tended to decrease. Light microscopy revealed no significant renal lesions, but transmission electron microscopy demonstrated increased cytosomes with myeloid figures (cytosegresomes) in the proximal tubule cells of treated dogs. These structures are characteristic markers of gentamicin. therapy. In addition, the proximal tubules of treated dogs contained single membrane limited vesicles with granular proteinaceous material; a structure not previously reported to be associated with aminoglycoside nephrotoxicity. The significance and relationship of these vesicles to the pathogenesis of gentamicin toxic nephropathy is not known. This study suggests that a single moderate dose of gentamicin is nephrotoxic in the beagle as judged by functional and morphological criteria.

Morphological and functional aspects of experimental gentamicin nephrotoxicity in young beagles and foals

A toxic nephropathy induced by gentamicin was investigated in young beagles and foals. Preliminary results indicated that a single 15 mg/kg dose of gentamicin administered to beagles produced subclinical functional and morphological changes in the kidney. Light histological lesions of aminoglycoside nephrotoxicosis were detected in all foals given gentamicin, suggesting an enhanced susceptibility of young horses to clinical renal dysfunction.

Determination of Cerebrospinal Fluid Gentamicin in the Beagle Using an Indwelling Cerebral Ventricular Cannula

This study compared the concentrations of gentamicin in the blood and cerebrospinal fluid (CSF) of young beagles. Indwelling cannulas were surgically implanted into the external jugular vein and the left lateral cerebral ventricle of two 5-month-old beagles. Gentamicin was given intravenously (10 mg/kg) and CSF and blood samples were taken. This was repeated in 1 dog three times over 42 days. CSF collected 2 weeks after cannula implantation was cytologically normal. Significant levels of gentamicin were detected in the CSF shortly after injection in the absence of inflammation. Levels persisted when inflammation was present. The use of an indwelling ventricular cannula was effective for the long-term monitoring of CSF drug levels.

Dynamic interfaces for computer-based simulations in pharmacology

A number of phenomena that are of fundamental importance to students of pharmacology (the science of drug action) have been modeled using computer simulations. We have created a series of models and interfaces which allow the student to alter certain relevant variables which may be altered while the models are running. The model provides information on a simulated real time basis, both by numbers and plotting of certain data. We suggest that his ability to alter the behavior of, for example, a model of the human body absorbing and eliminating a drug, has important pedagogical implications regarding experiential learning and student motivation. More complex models of simulated real time situations of more complex biological systems can be anticipated in the near future. It can also be anticipated that computer based learning will contribute more toward multi-functional teaching in the future.