Design, synthesis, and pharmacokinetic evaluation of a chemical delivery system for drug targeting to lung tissue.

We espouse the application of a novel chemical delivery system (CDS) approach to a delivery mechanism for drug targeting to lung tissue using the 1,2-dithiolane-3-pentyl moiety of lipoic acid as the "targetor moiety". The synthesis and the physicochemical and pharmacokinetic evaluation of a CDS modeling the lipoyl and other ester derivatives of chlorambucil (an antineoplastic agent) and cromolyn (a bischromone used in antiasthma prophylaxis) as compared with their respective parent drugs are described. The chlorambucil CDS was synthesized by esterifying the alcohol derivative of lipoic acid with chlorambucil using dicyclohexylcarbodiimide as the coupling agent. The cromolyn CDS was prepared by a multistep synthetic procedure culminating in the reaction of the alkyl bromide derivative of lipoic acid with the disodium salt of the bischromone compound. All the esters were highly lipophilic unlike the parent compounds. The in-vitro kinetic and in-vivo pharmacokinetic studies showed that the respective CDSs were sufficiently stable in buffer and biological media, hydrolyzed rapidly into the respective active parent drugs, and significantly enhanced delivery and retention of the active compound to lung tissue in comparison with the underivatized parent compounds used in conventional therapy.

Pharmacokinetics and bioavailabilities of hymecromone in human volunteers.

Specific and ultrasensitive reverse-phase HPLC assays of the choleretic and biliary antispasmodic hymecromone (down to 0.05 ng ml-1) and its glucuronide, using fluorimetric detection, and sulfate metabolites using UV detection, were developed. Sodium salt solutions of 400 mg (over 3 min) and 800 mg (over 5 min) were infused i.v. into 6-8 normal human volunteers. The half-life of the major rate constant averaged 28 +/- 2 min (SE). Subsequently, less than 0.8 per cent of the dose was eliminated with terminal half-lives of 70-359 min. The apparent volume of distribution of hymecromone, referenced to the total plasma concentration, averaged 20.8 +/- 1.41 (Vc, central compartment volume) and 36.4 +/- 2.11 (Vss steady state volume). Hymecromone's total body clearance averaged 1413 +/- 89 ml min-1. The pharmacokinetics of hymecromone were dose-independent. Only 0.3 +/- 0.3 per cent unchanged hymecromone was renally excreted. Mostly dose-independent glucuronidated drug (93 +/- 4 per cent of the dose) was excreted in the urine; a smaller amount was renally excreted as the sulfate (1.4 +/- 0.3 per cent of the dose). The oral bioavailability estimated from the relative areas under the hymecromone plasma concentration-time curves following oral and i.v. administration of hymecromone to six volunteer subjects showed no dose-dependence and was 1.8 +/- 0.6 per cent. However, an anomalous c. 200 per cent of the glucuronide produced by i.v. hymecromone was produced from orally administered hymecromone as determined from the ratio of the AUC values of glucuronide obtained after peroral and i.v. administration of the same dose of hymecromone to demonstrate a high first-pass effect and implicate renal glucuronidation.

Surgically affected sulfisoxazole pharmacokinetics in the morbidly obese.

Intestinal bypass surgery in 4 morbidly obese female (110-150 kg) had no permanent effect on the rate or amount of sulfisoxazole absorption. The loss of weight up to 44 per cent within an individual over a year's time had no significant effect on the apparent volumes of distribution or other pharmacokinetic parameters of sulfisoxazole and its N4-acetylsulfisoxazole metabolite. Dosing of this drug on a mg kg-1 basis is contraindicated. Renal clearances of sulfisoxazole were reasonably constant within a study but those of the N4-acetylsulfisoxazole decreased with time. Integrated pharmacokinetic models were applied to plasma and urine data to estimate the metabolic clearance of sulfisoxazole and the apparent volume of distribution of the N4-acetylsulfisoxazole. Sulfisoxazole solution is absorbed readily by primarily a zero order process after a short lag period, indicative of rate-determining gastric emptying. The classical Bratton-Marshall assays were compared with an HPLC assay of both drug and metabolite. There was greater confidence in plasma levels of the metabolite from the HPLC method.