Francis L. S. Tse

Effect of Current Magnitude and Drug Concentration on lontophoretic Delivery of Octreotide Acetate (Sandostatin®) in the Rabbit

The effect of current magnitude and drug concentration on transdermal iontophoretic delivery of octreotide acetate (Sandostatin®) was examined in the rabbit. Plasma samples were collected over 24 hours and octreotide concentrations were determined by a radioimmunoassay. Without an electrical current, negligible plasma concentrations of octreotide were obtained. Following initiation of iontophoresis, plasma concentrations of octreotide increased rapidly, although did not sustain at a plateau level during the dosing period. Octreotide concentrations declined rapidly after removal of the device. Increasing the electrical current from 50 µA/cm2 to 150 µA/cm2 yielded a proportional increase in the delivery. Increasing the drug concentration in the device from 2.5 mg/mL to 5 mg/mL resulted in approximately proportional increase in plasma octreotide concentrations; however, further increase in plasma concentrations was not observed for drug concentrations beyond 5 mg/mL. lontophoretic delivery at the conditions which yielded the highest octreotide concentrations in this study (5 mg/mL solution at 150 µA/cm2 for 8 hours) yielded an apparent bioavailability (which represents an underestimate of the absolute bioavailability determined when the patches are run to exhaustion) of approximately 8%.

Treatment with sisomicin of complicated urinary tract infections in patients with varying degrees of renal function impairment, pharmacokinetics and dosage adjustment.

SummaryThe efficacy, tolerance and pharmacokinetics of the new aminoglycoside antibiotic sisomicin, have been studied in 29 elderly male patients with varying degrees of renal function impairment and suffering from complicated urinary tract infections. The antibiotic was equally effective in patients with normal and impaired renal function and a cure (negative urine culture at one week follow-up) of 56% was obtained. There was little apparent toxicity with the dosage regimens used, although serum creatinine values were statistically but not clinically significantly increased in some patients following treatment. Serum half-lives of sisomicin were prolonged in cases of impaired renal function but accumulation of antibiotic could be prevented by varying dosing intervals between 8 and 24 hours based on serum creatinine values. There was good correlation between serum creatinine and sisomicin serum half-life values and a practical method is described for dose adjustment based on the relationship between serum half-lives and serum creatinine concentrations.ZusammenfassungDie Wirksamkeit, Verträglichkeit und Pharmakokinetik des neuen Aminoglykosid-Antibiotikums Sisomicin wurde an 29 älteren männlichen Patienten mit unterschiedlichen Graden der Nierenfunktionsstörung untersucht, die an komplizierten Harnwegsinfektionen litten. Das Antibiotikum war bei Patienten mit normaler und gestörter Nierenfunktion im gleichen Maße wirksam und in 56% der Fälle wurde eine Heilung erzielt (negative Harnkultur bei der Kontrolluntersuchung nach einer Woche). In den angewandten Dosierungen zeigte sich nur eine unbedeutende Toxizität, obgleich bei einigen Patienten die Serumkreatininwerte im Anschluß an die Behandlung statistisch, jedoch nicht klinisch signifikant erhöht waren. In Fällen von Nierenfunktionsstörung waren die Halbwertszeiten von Sisomicin im Serum verlängert, doch konnte eine Kumulation des Antibiotikums durch Variieren der Dosierungsintervalle zwischen 8 und 24 Stunden auf der Grundlage der Serumkreatininwerte verhindert werden. Es bestand eine gute Wechselbeziehung zwischen den Serumkreatininwerten und den Halbwertszeiten von Sisomicin im Serum und es wird eine praktische Methode zur Anpassung der Dosis auf der Grundlage des Verhältnisses zwischen Halbwertszeiten im Serum und Kreatininkonzentrationen im Serum beschrieben.

Pharmacokinetics of Compound 58–112, a Potential Skeletal Muscle Relaxant, in Man

Abstract: The pharmacokinetics of 4‐[(3‐methoxyphenyl)methyl]‐2,2,6,6‐tetramethyl‐1‐oxa‐4‐aza‐2,6‐disilacyclohexane (Sandoz compound 58–112), a new chemical entity with a unique myotonolytic effect, was studied in 12 healthy male volunteers who received an oral dose of 50 or 100 mg of the 14C‐labeled drug. Serial blood and breath samples and complete urine and feces were collected for 120 hours after dosing. All samples were analyzed for total radioactivity while the blood and urine were also assayed for unchanged compound 58–112. Measurable blood radioactivity levels were observed at 0.5 hour, and peak concentrations were attained at 1 to 2 hours after dosing. The absorption of the radioactive doses was complete and appeared linear in the 50–100 mg range, as indicated by blood 14C levels that were proportional to the dose. The 50‐ and 100‐mg doses also resulted in virtually identical excretion patterns, with 95 per cent of the administered radioactivity recovered within 9 hours, almost exclusively in the urine. However, the disproportionately higher blood concentrations of unchanged compound 58–112 after the 100‐mg dose could suggest saturable presystemic metabolism in the liver. Simultaneous fitting of all data in the 100‐mg dose study to a pharmacokinetic model showed that unchanged compound 58–112 was distributed into a central and a peripheral compartment and was eliminated entirely by metabolism, the distribution and elimination half‐lives being 0.5 and 3.9 hours, respectively. The metabolite(s) was distributed into one homogeneous space, and its elimination half‐life was 0.1 hour, with a renal:fecal clearance ratio of ∼96:4.

Factors contributing to variability in drug pharmacokinetics. I. Absorption.

Apart from the physical and chemical properties of a drug, and also the dosage form in which it is presented, many other factors may affect the absorption of orally administered compounds and give rise to variable systemic availability. Three such factors, gastrointestinal (GI) disease, drug‐drug interactions, and drug‐food interactions are considered here.

Relative bioavailability of prednisone and prednisolone in man.

The synthetic corticosteroids prednisone and prednisolone are both used internally for their anti-inflammatory activity in a wide spectrum of diseases. Prednisone is pharmacologically inactive until reduced at the 1 1-keto position to form prednisolone by the enzyme 11-phydroxydehydrogenase (Jenkins & Sampson 1967; 1967; Lewis et al 1971). The most important site for this conversion is the liver (Jenkins 1966; Powell & Axelsen 1972). Although hepatic conversion of prednisone to prednisolone is extensive and the two compounds are generally considered to be therapeutically equivalent when used systemically, there is little quantitative information on the relative bioavailability of active prednisolone from the two drug forms. One report showed that orally dosed prednisone resulted in lower circulating prednisolone concentrations compared with equivalent oral doses of prednisolone in three normal subjects, although similar concentrations of prednisolone were obtained from the two drug forms in two patients with liver disease (Jenkins & Sampson 1966). A second report describes significantly lower circulating concentrations of prednisolone in 22 patients with liver disease receiving prednisone, than in the same patients receiving prednisolone, but no differences after dosing the two drug forms in normal subjects (Jenkins 1966). A case of therapeutic inequivalence between prednisone and prednisolone has been reported (Levy et al 1964), although it is uncertain whether the inequivalence was due to poor bioavailability of the prednisone formulation or inability of the patieRt to metabolize prednisone (Sugita & Niebergall 1975). This communication describes a pilot study comparing the bioavailability of commercial brands of prednisone and prednisolone in a human subject. Methods. The subject, a healthy 42 year old male weighing 77 kg with normal liver and kidney function, received single oral doses of 30 mg (6 x 5 mg tablets) of prednisolone (Delta-Cortef, Upjohn) or 30 mg (6 x 5 mg tablets) of prednisone (Prednisone U.S.P., Phillips Roxane). Two single doses of each drug were given, alternating prednisolone and prednisone, at approximately two weeks apart. Tablets were administered at 8 a.m. on an empty stomach (overnight fast) with 200 ml of water. Serial venous blood samples were taken and plasma prednisolone was measured using the gas-chromatographic method of Bacon & Kokenakes (1969), with slight modifications (Tse & Welling 1977).

Effect of Food on the Bioavailability of SDZ DJN 608, an Oral Hypoglycemic Agent, from a Tablet and a Liquid-Filled Capsule in the Dog

AbstractPurpose. The effect of food on the bioavailability of SDZ DJN 608, a D-phenylalanine derivative, was investigated in three mature, male beagle dogs. Methods. Each dog received, under fasting and postprandial conditions, a 30 mg oral dose as a tablet (T) and a liquid-filled capsule (LC). Additionally, a 5 mg intravenous dose was given in the fasting state. Doses in the same dog were separated by 1-week washout periods. Serial plasma samples were collected for 24 h postdose and analyzed for SDZ DJN 608 using HPLC. Model-independent pharmacokinetic parameters were compared between treatments by 3-way ANOVA. In vitro dissolution profiles of T and LC were generated using the USP paddle method. In addition, the transport of SDZ DJN 608 through a Caco-2 cell monolayer was examined at concentrations of 0.1 and 1 mM, in the absence and presence of an aromatic amino acid, L-α-methyldopa, the transport of which is mediated by the large neutral amino acid (LNAA) carrier. Results. In the dog, SDZ DJN 608 was rapidly absorbed. The peak plasma concentration (Cmax) averaged higher, and the peak time (tmax) shorter, after LC than T, though the differences were not statistically significant. This finding is consistent with in vitro dissolution data showing that, at both pH 1.2 and pH 6.8, the dissolution rate of LC was faster than that of T. No significant difference in the area under curve (AUC) was observed between LC and T, the absolute bioavailability of both being complete in the fasting state. Whereas the presence of food showed little effect on the tmax and Cmax of either dosage form, it significantly reduced the AUC, the effect (ca −20%) being not different between LC and T. In the Caco-2 model, the mucosal-to-serosal permeability of SDZ DJN 608 was independent of concentration and unaffected by L-α-methyldopa, suggesting passive diffusion of the former. Conclusions. Food had little effect on the absorption rate but significantly reduced the bioavailability of SDZ DJN 608 regardless of the dosage form. This effect is unlikely to be caused by inhibition of the transepithelial transport of SDZ DJN 608 by amino acids in the diet.

Effect of food, fluid and dosage form on the absorption of 52–522, a potential antianxiety agent, in the dog

The absorption of 52–522 in the dog was studied by measuring blood concentrations of radioactivity after single oral doses of [14C] 52–522 in a capsule with and without water, also as a food‐drug mixture, and a solution in polyethylene glycol 400. Absorption was rapid, and its rate moderate with no significant differences in peak times among treatments. The extent of absorption was lowest after the capsulated [14C] 52–522. The solution dose gave elevated blood concentrations, that were statistically significantly different when compared with the capsules. Hence, it appears that the absorption of [14C] 52–522 is governed by the degree of dispersion of drug in the dosage form.

Enterohepatic circulation of radioactivity following an oral dose of [14C]temazepam in the rat

The enterohepatic circulation of radioactive material after administering [14C]temazepam was evaluated in three sets of male Wistar strain rats connected in pairs by bile duct‐duodenum cannulae. After a single oral dose (10 mg kg−1) to the donor rat, the excretion of radioactivity in the urine and faeces of both rats and in the bile of the recipient rat was determined. Mean total recovery of the administered radioactivity was 92·2%. Based on the amount remaining in the donor rat (gastrointestinal tract and faeces), 81·7% of the dose was absorbed by the donor. The total amount recovered from the recipient, 69·4% of original dose (85·1% of donors absorbed dose), represented the amount excreted in the donors bile. Similarly, 54·1% of the original dose (77·9% of the transferred biliary excretion from donor) was reabsorbed by the recipient, and the biliary excretion from this animal (45·9% original dose) accounted for 86·% of the amount reabsorbed.

Interspecies similarities in the disposition of 3H-dihydroergotamine following subcutaneous administration in man and rabbits

SummaryThe disposition of dihydroergotamine methanesulfonate following single subcutaneous doses was studied in man and the rabbit using radiotracer techniques.3-Dihydroergotamine was almost immediately and completely absorbed from the injection site; peak blood radioactivity levels were attained within I h of drug administration in both species. The disappearance of radioactivity from blood was biphasic, with t1/2,α and t1/2,β values of 2.9 and 16.9h, respectively, in man and 2.9 and 14.7h, respectively, in the rabbit. Apparent volumes of distribution were 18.9 Liter/kg in man and 30.4 Liter/kg in the rabbit. The excretion pattern of dihydroergotamine and its metabolites was also similar for the two species, with biliary elimination being the predominant route. At 4–5 days postdosing, 80-85%of the administered radioactivity was recovered in the feces and urine. The rabbit appears to be an adequate animal model for the study of dihydroergotamine pharmacokinetics in man.

Sisomicin treatment of complicated urinary tract infections

The purpose of this presentation is twofold: firstly, to present our experience with sisomicin in the treatment of complicated urinary tract infections; secondly, to summarize the results of our clinical trials with this antibiotic in patients with normal and impaired renal function, with particular reference to the determination of dosage and dosage intervals in cases of impaired renal function. We first treated 36 male patients (average age 71 years) with complicated urinary tract infection, but with normal renal function. These were divided into three groups of 12 each, with one group receiving sisomicin 0.5 mg/kg every eight hours, while the other two received 0.75 mg/kg and 1 mg/kg respectively every eight hours. Each group was treated for a total of seven days. Defining cure as a negative urine culture two to three weeks after cessation of antibiotic therapy, we obtained a cure rate of 50, 75 and 58% for the three respective groups. Sisomicin was well tolerated locally and systemically. In our second clinical trial we treated 29 males, all with complicated urinary tract infections, and again divided the patients into three groups, but this time according to renal function. Patients in Group A had a serum creatinine of 1.4 mg/ 100 ml, with an average creatinine clearance of 82 ml/min. Group B had a serum creatinine of 1.5 to 2.5 rag/100 ml and an average creatinine clearance of 34 mI/min, and Group C had a serum creatinine of 2.5 mg/100 ml and an average clearance of 18 ml/min. All patients received 1 mg/kg of sisomicin intravenously (IV) the first day, followed by 1 mg/kg intramuscularly (IM) every eight hours (Group A), every 12 hours (Group B) and every 24 hours (Group C) for seven days. Again sisomicin was well tolerated. It was equally effective in patients with normal and impaired renal function and a cure rate of 56% was obtained. The sisomicin urine concentrations up to 24 hours following a single IV injection in all three groups of patients were many times higher than the MIC values for most gram-negative organisms found in urinary tract infections. There was a good correlation between the sisomicin serum half-life and the serum creatinine level. The dosage intervals for administration of sisomicin in patients with normal renal function should be approximately eight hours, increased in azotemic patients by multiplying this interval by the serum creatinine (in rag/100 ml) or, if the dosage interval is kept unchanged, by dividing the dosage by the serum creatinine. Thus, a patient with a serum creatinine of 3 rag/100 ml would require 1 mg/kg every 24 hours. Since we found high sisomicin concentrations in the urine 8 to 16 and even 16 to 24 hours following IM administration, we proceeded to our next study in which we compared two groups of patients, again with complicated urinary tract infections, using two different dosages of sisomicin. One group received 75 mg of sisomicin every 12 hours, the other 100 mg every 24 hours. The cure rate, defined as a negative urine culture one week after treatment, was 75 % in both groups. In our last study we compared sisomicin with gentamicin in a prospective, randomized study of 100 patients with complicated urinary tract infections. Sisomicin (75 mg IM) was administered every 12 hours for seven days and gentamicin (80 mg IM), every 8 hours for seven days. Both groups were comparable in terms of age, other demographic factors, the urinary tract pathology and causative bacteria.