Anthony R. DiSanto

Pharmacokinetics of Erythromycin in Normal and Alcoholic Liver Disease Subjects

Abstract: The objective of this study was to compare the pharmacokinetic behavior of erythromycin in normal volunteers with that in subjects with alcoholic liver disease. Six normal volunteers received 500 mg erythromycin as an intravenous infusion or as two 250‐mg enteric‐coated tablets in a crossover fashion. The pharmacokinetics of erythromycin after intravenous administration was best described as a two‐compartment model. The elimination half‐life was 1.6 ± 0.7 hours (mean ± S.D.) after the intravenous dose and 2.0 ± 0.7 hours after the oral dose. In patients with alcoholic liver disease the elimination half‐life after oral administration of two 250‐mg enteric‐coated tablets was 3.2 ± 0.5 hours, significantly different from that in normal subjects, probably due to impaired metabolism. The difference in half‐life does not require dosage adjustment in this patient population. The systemic availability of erythromycin was 33.5 per cent (range 10.5 to 79.3 per cent).

Pressor Response to Tyramine after Single 24-Hour Application of a Selegiline Transdermal System in Healthy Males

Orally administered selegiline hydrochloride is a selective monoamine oxidase type B inhibitor at the recommended regimen of 10 mg/day, but it loses selectivity at higher doses. In bypassing first‐pass metabolism, a 24‐hour application of transdermally administered selegiline (7.8 mg/24 hr) yields fifty times greater systemic exposure than is provided by single oral doses. The current study was designed to demonstrate that, similar to the oral regimen, transdermally administered selegiline is devoid of the pressor effects associated with tyramine and classic monoamine oxidase type A inhibitors. A single‐blind, staggered, parallel‐group study of pressor response to tyramine during a single 24‐hour application of one‐quarter, one‐half, or one selegiline transdermal system relative to baseline (drug‐free) response to tyramine was conducted in three groups, each with five healthy male volunteers. The end point of pressor response was declared if a participants systolic blood pressure rose by >30 mmHg, heart rate decreased by >25 bpm with an associated >20‐mmHg rise in systolic blood pressure, or a clinically significant change was observed in the electrocardiogram. Doses up to 600 mg were administered during the baseline phase and up to 200 mg during the active‐treatment phase. Participants received escalating tyramine doses every 4 hours until the maximum or threshold dose was achieved. Doses up to 200 mg were tolerated without apparent increase in sensitivity in participants receiving one‐quarter, one‐half, or one selegiline transdermal system. All participants completed the trial, and no significant adverse events were reported. Monoamine oxidase type B inhibition was complete (100%) by 12 hours after initial application in all treatment groups while plasma levels of 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) after 24‐hour application were unaffected relative to baseline. These results suggest that systemic selegiline levels may not predict the propensity for a hypertensive crisis associated with presumed nonselective doses and that the avoidance of peripheral monoamine oxidase type A inhibition in the gut via the selegiline transdermal system may provide a safe vehicle for administering selegiline at plasma levels beyond that which can be safely obtained after oral administration. These findings will need to be confirmed in a long‐term dose setting.

TOXICOKINETIC EVALUATION OF A SELEGILINE TRANSDERMAL SYSTEM IN THE DOG

The toxicology and toxicokinetics of a selegiline transdermal system (STS) were evaluated in a 3 month dog study of daily 24 h applications of placebo 4, 8, or 12 STSs in 32 male and 32 female beagle dogs. Each STS delivered approximately 5 mg selegiline over 24 h. No drug-related signs of toxicity were noted in any group with respect to clinical observations, dermal effects, body weight, food consumption, hematology, urinalysis data, or ophthalmoscopic or electrocardiographic examinations. Clinical chemistry data revealed no consistent adverse effects except for an increase in alanine aminotransferase in dogs receiving 8 and 12 STSs. Histological evaluation of tissues revealed the presence of pigment in the Kupffer cells of dogs treated with 8 and 12 STSs. There were no pathology findings suggestive of hemolysis or cholestasis. The no-effect level (NOEL) was 4 STSs (2.9 mg kg-1 d-1). There were no degenerative or life-threatening toxic effects up to 12 STSs (8.5 mg kg-1 d-1). Gender-related differences in steady-state plasma levels were not observed. Steady-state plasma concentrations were similar to maximum plasma concentrations obtained in single-dose studies, suggesting that drug accumulation was not evident. Simulation of systemic exposure following oral administration of 16.8 mg kg-1 d-1 from previous toxicology studies indicated that selegiline exposure following 12 STSs is sixfold greater while N-desmethylselegiline, L-amphetamine, and L-methamphetamine exposure is 0.5, 0.15, and 0.14 times the exposure in the oral study. The threefold difference in NOEL between oral and transdermal studies in the dog (0.8 versus 2.9 mg kg-1 d-1) is probably related to greater L-amphetamine and L-methamphetamine exposure following oral administration. The reduction in metabolite formation, relative exposure of selegiline in the dog at the NOEL compared to oral toxicology studies, and margin of safety provided, given that the expected clinical dose is less than the dosage of oral Eldepryl (0.15 mg kg-1 d-1), documents the safety of the selegiline drug substance and indicates that additional toxicologic findings with the STS may not be expected.

Pharmacokinetic Interpretation of Plasma Cortisol and Cortisone Concentrations Following a Single Oral Administration of Cortisone Acetate to Human Subjects

The pharmacokinetic and biopharmaceutic profiles of a single dose of oral cortisone acetate were developed for 23 healthy normal adult volunteers using cortisone and cortisol plasma concentration data. Cortisone acetate was rapidly absorbed and converted to the therapeutic moiety cortisol. There was a linear increase in plasma concentrations and, therefore, areas under plasma concentration-time curves with increasing doses of 5, 10, and 25 mg. Twenty-five-mg doses given as 1 x 25 mg or 5 x 5 mg were found to be bioequivalent. The increased efficacy of oral over intramuscular cortisone acetate can be attributed to the increased conversion to cortisol as a result of first-pass metabolism following oral dosing.

The Effect of Colestipol Hydrochloride on the Bioavailability and Pharmacokinetics of Clofibrate

Since it has been reported by several authors that colestipol HCl and clofibrate have an additive effect in lowering serum cholesterol levels, it was felt advisable to evaluate the blood levels of clofibrate when given simultaneously with colestipol HCl to see whether there was any evidence for drug interaction between the two products that might dictate a need for separation of their administration time. After concomitant single-dose administration, the serum p-chlorophenoxyisobutyric acid levels, bioavailability parameters, and pharmacokinetic parameters investigated provided no evidence for an interaction and suggested that colestipol and clofibrate can be administered concomitantly or at separated in tervals according to whichever dosage regimen is deemed advisable by the physician.

The clinical pharmacology of methylprednisolone sodium phosphate. I. Intramuscular route of administration.

Intramuscularly administered methylprednisolone sodium phosphate (Medrol Stabisol) in single doses of 40, 80, or 160 mg (methylprednisolone equivalents) had a similar effect as the same doses of methylprednisolone sodium succinate (Solu-Medrol) with regard to eosinophil suppression, elevation of glucose, white blood count differential shifts (lympholytic effect), urinary excretion of sodium and potassium, and localized (pain) and systemic side effects. The average plasma methylprednisolone concentration was approximately 20% higher after the intramuscular administration of methylprednisolone sodium phosphate than after methylprednisolone sodium succinate. The differences in plasma methylprednisolone levels produced by the two esters suggest that either hydrolysis of the succinate ester occurs more slowly or the succinate ester distributes more extensively. This difference in plasma level, however, is not reflected in any other pharmacologic evaluation of the two esters, e.g., both eosinophil depression and hyperglycemic response were identical. No clinically significant changes in the vital signs, standard hematology, and clinical chemistry parameters evaluated were noted after 21 successive doses (q.i.d. for five days with one dose in the morning of day 6) of 80 mg methylprednisolone sodium phosphate. An increase was noted in the systolic blood pressure from a pretreatment mean of 113 mm Hg to a posttreatment mean of 123 mm Hg and an increase in the body weight from a pretreatment mean of 177 pounds to a posttreatment mean of 183 pounds. No signs of adrenal suppression were found as judged by plasma cortisol and ACTH levels. Six (6/12) subjects of the methylprednisolone sodium phosphate group, one (1/12) subject of the vehicle group, and one (1/12) subject of the placebo (sterile saline) group reported the following systemic side effects: gas in stomach, headaches, anorectal itching, and dryness of itching of the skin. No trend was observed for any side effect reported. In these double-blind, randomized studies, single (40, 80, and 160 mg) and multiple (80 mg) intramuscular doses of methylprednisolone sodium phosphate were tolerated in healthy volunteers as well as the same doses of methylprednisolone sodium succinate and similar volumes of vehicle or placebo.

Chlorphenesin Carbamate Serum Levels During Subchronic Administration to Human (Normal) Volunteers

T lIE results of a subchronic tolerance study with chiorphenesin carbamate in healthy volunteers at a dose of 3200 mg daily for eight weeks was previously reported by Novak et al.’ As reported by these investigators, no clinically significant laboratory or vital sign changes from pretreatment values or between drug and placebo groups were noted. Concomitant with the above study, blood samples for the determination of serum levels of chlorphenesin carbamate were also collected. The results of these serum level determinations in ten subjects selected from the study group are presented here.

The clinical pharmacology of methylprednisolone sodium phosphate. II. Intravenous route of administration.

Doses of 1, 3, 5, 10, 20 and 30 mg/kg of methylprednisolone sodium phosphate (MSP) or methylprednisolone sodium succinate (MSS) or similar volumes of vehicle or sterile saline administered intravenously at random in a double-blind fashion to healthy volunteers were well accepted, tolerated, and safe when given as a bolus over a 10-min period. MSP and MSS when administered in equal doses had a similar effect on eosinophil suppression, glucose elevation, WBC differential shifts (lympholytic effect), urinary excretion of sodium and potassium, and plasma cortisol concentrations (fasting or after ACTH challenge). No clinically significant drug-related changes were found in the vital signs, EKGs, EEGs, intraocular pressure, or standard clinical laboratory evaluations. With the 30-mg/kg dose, side effects were observed. In the multiple-dose iv study, no adverse drug reaction was noted after 80- or 40-mg single doses of MSP or MSS. Eosinopenia and hyperglycemia occurred within 2 hr postinjection. A tendency to return toward pretreatment values was noted within 24 hr after the last injection. Both forms of methylprednisolone when given in equivalent doses caused eosinopenia and hyperglycemia of a similar magnitude. No statistically significant differences were found among the four treatment groups in the EKGs PR, QRS, QT intervals, and PR rates. MSP when given in 40-mg iv doses was as well tolerated as MSS. However, 80-mg doses of MSP were not tolerated as well as 40-mg doses of MSP or 80-mg doses of MSS.