ABSTRACT
Systemic and oral clearances of alfentanil (ALF) are in vivo probes for hepatic and first-pass cytochrome P450 (CYP) 3A. Both ALF single-point plasma concentrations and miosis are surrogates for area under the concentration-time curve (AUC) and clearance and are minimal and noninvasive CYP3A probes. This investigation determined ALF sensitivity for detecting graded CYP3A induction and compared it with that of midazolam (MDZ). Twelve volunteers (sequential crossover) received 0, 5, 10, 25, or 75 mg oral rifampin for 5 days. MDZ and ALF were given intravenously and orally on sequential days. Dark-adapted pupil diameter was measured with blood sampling. Graded rifampin decreased plasma MDZ AUCs to 83, 76, 62, and 59% (intravenous (i.v.)) and 78, 66, 39, and 24% (oral) of control. Hepatic and first-pass CYP3A induction were detected comparably by plasma MDZ and ALF AUCs. Single ALF concentrations detected all CYP3A induction, whereas MDZ was less sensitive. ALF miosis detected induction of first-pass but not hepatic CYP3A.
Subject(s)
Alfentanil/pharmacology , Analgesics, Opioid/pharmacology , Cytochrome P-450 CYP3A/biosynthesis , Liver/drug effects , Liver/enzymology , Miosis/chemically induced , Administration, Oral , Adolescent , Adult , Alfentanil/administration & dosage , Analgesics, Opioid/administration & dosage , Area Under Curve , Biological Availability , Cross-Over Studies , Enzyme Induction/drug effects , Female , Half-Life , Humans , Hypnotics and Sedatives/blood , Hypnotics and Sedatives/pharmacology , Injections, Intravenous , Kinetics , Leprostatic Agents/pharmacology , Male , Midazolam/blood , Midazolam/pharmacology , Rifampin/pharmacology , Smoking/metabolism , Young AdultABSTRACT
Oral phenytoin is used widely for the treatment of convulsive disorders and about half the patients treated develop gingival overgrowth as a side effect. The apparent stimulatory effect has prompted its assessment in wound healing. Studies have shown topical phenytoin to promote healing of decubitus ulcers, venous stasis ulcers, diabetic ulcers, traumatic wounds, burns, and leprosy trophic ulcers. The mechanism of action has been postulated to be multifactorial. The present literature indicates that topical phenytoin deserves further investigation as a wound-healing agent in controlled dose-finding clinical trials.
Subject(s)
Phenytoin/therapeutic use , Wound Healing/drug effects , Abscess/drug therapy , Administration, Topical , Burns/drug therapy , Collagenases/biosynthesis , Connective Tissue/drug effects , Diabetic Foot/drug therapy , Drug Evaluation , Enzyme Induction/drug effects , Fibroblasts/drug effects , Granulation Tissue/drug effects , Humans , Keratinocytes/drug effects , Phenytoin/administration & dosage , Phenytoin/pharmacology , Powders , Skin Ulcer/drug therapy , Wounds, Penetrating/drug therapyABSTRACT
Rifapentine (R773, DL473) is a long-acting antituberculous drug used in China. In our experiments we have found some manifestations of induction of hepatic mixed function oxidase system in mice following pretreatment with rifapentine or phenobarbital. Both rifapentine and phenobarbital significantly increased the rate of antipyrine and pentobarbital metabolism in vivo. They also increased liver weight, the content of liver microsomal protein and cytochrome P-450, the activity of NADPH-cytochrome C reductase and NADPH oxidase. SDS-polyacylamide gel electrophoresis showed that the relative proportions of some polypeptide bands in mice microsomal fraction were significantly changed following rifapentine or phenobarbital pretreatment. The results indicate that rifapentine, like phenobarbital, is a potent inducer of hepatic mixed function oxidase system in mice and that it should be used carefully in clinical therapy, when combined with other drugs.