Clonidine is a centrally active antihypertensive agent effective in the treatment of mild, moderate and severe hypertension, alone or in combination with other drugs. Use of oral clonidine has often been limited by side effects which include dry mouth and drowsiness. Transdermal clonidine was therefore developed as an alternative to oral therapy. Ideally, a drug administered at a constant rate into the systemic circulation should attain steady-state concentrations with less peak-to-trough fluctuation than that associated with intermittent oral dosing. In theory, transdermal administration should thus minimise the adverse effects associated with peak plasma drug concentration, while avoiding the potential for decreased efficacy associated with trough levels. Clonidine has been incorporated into a small, pliable adhesive cutaneous delivery device designed to provide therapeutically effective doses of drug at a constant rate for at least 7 days. The transdermal therapeutic system is a laminate consisting of an external film impermeable to moisture and to the drug, a thin layer of active drug dispersed within a highly drug-permeable matrix, a membrane with a controlled intrinsic permeability regulating the rate of delivery of drug to the skin, and an adhesive coating that attaches the system to the skin surface. The permeation of drug through the skin occurs primarily by diffusion. Application of the clonidine transdermal system to both normotensive and hypertensive subjects has consistently reduced systolic and diastolic blood pressures. Maximum reduction in blood pressure occurs 2 to 3 days after initial application, and is maintained for at least 7 days or until the system is removed. The rate at which clonidine is presented to the skin surface is controlled by the microporous membrane: this rate is the same for all strengths of transdermal clonidine, the amount of clonidine released being proportional to its surface area. Thus, the daily dose is regulated by the area of skin covered. Typically, steady-state plasma concentrations are reached on the fourth day after initial transdermal system application. The lack of dose dependency in half-life and renal clearance estimates emphasise that the transdermal absorption of clonidine is linear. The plasma clonidine concentration produced by a particular transdermal dose varies considerably between individuals as a result of interindividual variation in renal clearance. For this reason, it is recommended that dosages be titrated up from the smallest system (3.5 cm2) until the desired pharmacological effect has been obtained.(ABSTRACT TRUNCATED AT 400 WORDS)

The effects of tipranavir/ritonavir (TPV/r) on hepatic and intestinal P-glycoprotein (P-gp) and cytochrome P450 (CYP) enzyme activity were evaluated in 23 volunteers. The subjects received oral (p.o.) caffeine, warfarin + vitamin K, omeprazole, dextromethorphan, and midazolam and digoxin (p.o. and intravenous (i.v.)) at baseline, during the first three doses of TPV/r (500 mg/200 mg b.i.d.), and at steady state. Plasma area under the curve (AUC) 0-∞ and urinary metabolite ratios were used for quantification of protein activities. A single dose of TPV/r had no effect on the activity of CYP1A2 and CYP2C9; it weakly inhibited CYP2C19 and P-gp; and it potently inhibited CYP2D6 and CYP3A. Multiple dosing produced weak induction of CYP1A2, moderate induction of CYP2C19, potent induction of intestinal P-gp, and potent inhibition of CYP2D6 and CYP3A, with no significant effects on CYP2C9 and hepatic P-gp. Several P450/transporter single-nucleotide polymorphisms correlated with the baseline phenotype but not with the extent of inhibition or induction. Although mixed induction and inhibition are present, this approach offers an understanding of drug interaction mechanisms and ultimately assists in optimizing the clinical use of TPV/r.Cocktail phenotyping involves simultaneous, single-dose administration of marketed drugs (also known as probes) to measure the activity (or phenotype) of multiple hepatic and intestinal drug-metabolizing enzymes and transporters for rapid and efficient assessment of the drug interaction potential of a new compound. [1][2][3][4][5] The "Cooperstown 5 + 1 cocktail" consists of caffeine, warfarin, omeprazole, dextromethorphan, intravenous (i.v.) midazolam, and vitamin K (to negate warfarin's anticoagulant effect). 6 We have modified this approach to elucidate the specific influences of drugs on hepatic and intestinal proteins by evaluating enzyme activity NIH Public Access Author ManuscriptClin Pharmacol Ther. Author manuscript; available in PMC 2011 June 1. Published in final edited form as:Clin Pharmacol Ther. 2010 June ; 87(6): 735-742. doi:10.1038/clpt.2009.253. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript under baseline conditions in addition to conditions of both acute and chronic drug exposure. Oral (p.o.) midazolam and i.v. and p.o. digoxin were also added as probe substrates in order to measure hepatic + intestinal CYP3A activity, hepatic P-glycoprotein (P-gp) activity, and hepatic + intestinal P-gp activity, respectively. 7,8 The genotyping of cytochrome P450 (CYP) genes corresponding to enzymes investigated with phenotype probes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5/7/43) and P-gp (ABCB1) also allows for investigating genotype-phenotype correlations and determining genetic influences on drug interactions.We used this modified cocktail approach to investigate the drug interaction potential of tipranavir (TPV) administered along with low-dose ritonavir (RTV). TPV is a nonpeptidic protease inhibitor (PI) with potent activity against HIV-1-res...

The results of two randomized, single‐dose, crossover bioavailability studies are presented which describe the pharmacokinetics and oral bioavailability of nevirapine, a novel nonnucleoside antiretroviral drug. In the first study 12 healthy male volunteers received nevirapine 15 mg via short‐term i.v. infusion or orally as a 50 mg tablet or reference solution (50 mg/200 mL). Following the i.v. dose, nevirapine had a low systemic clearance (Mean±S.D., Cl=1.4±0.3 L/h) and a prolonged elimination phase (t1/2β=52.8±14.8 h; MRT=81.4±22.4 h). Nevirapine absolute bioavailability was 93±9% and 91±8% for the tablet and oral solution, respectively. In the second study, 24 healthy male volunteers were administered nevirapine as a 200 mg production‐line tablet or oral reference solution (200 mg/200 mL). There was no significant difference in bioavailability between the tablet and reference solution. Overall, comparison of the pharmacokinetic parameters between the 50 and 200 mg doses indicates that nevirapine is well absorbed at clinically relevant doses. The absorption profiles using deconvolution revealed no evidence of differential enzyme induction between the two doses or routes of administration following a single dose. Copyright © 1999 John Wiley & Sons, Ltd.

Loperamide (LOP) is a peripherally acting opioid receptor agonist used for the management of chronic diarrhea through the reduction of gut motility. The lack of central opioid effects is partly due to the efflux activity of the multidrug resistance transporter P-glycoprotein (P-gp) at the blood-brain barrier. The protease inhibitors are substrates for P-gp and have the potential to cause increased LOP levels in the brain. Because protease inhibitors, including tipranavir (TPV), are often associated with diarrhea, they are commonly used in combination with LOP. The level of respiratory depression, the level of pupil constriction, the pharmacokinetics, and the safety of LOP alone compared with those of LOP-ritonavir (RTV), LOP-TPV, and LOP-TPV-RTV were evaluated in a randomized, open-label, parallel-group study with 24 healthy human immunodeficiency virus type 1-negative adults. Respiratory depression was assessed by determination of the ventilatory response to carbon dioxide. Tipranavir-containing regimens (LOP-TPV and LOP-TPV-RTV) caused decreases in the area under the concentration-time curve from time zero to infinity for LOP (51% and 63% decreases, respectively) and its metabolite (72% and 77% decreases, respectively), whereas RTV caused increases in the levels of exposure of LOP (121% increase) and its metabolite (44% increase). In vitro and in vivo data suggest that TPV is a substrate for and an inducer of P-gp activity. The respiratory response to LOP in combination with TPV and/or RTV was not different from that to LOP alone. There was no evidence that LOP had opioid effects in the central nervous system, as measured indirectly by CO 2 response curves and pupillary response in the presence of TPV and/or RTV.Loperamide (LOP; Imodium, McNeil-PPC, Inc.) is a peripherally acting opioid receptor agonist that reduces gut motility and that is used for the management of chronic diarrhea (8,25). The principal metabolic fate of loperamide in humans involves oxidative N-dealkylation to N-demethyl-loperamide as the principal metabolite. In human liver microsomes, cytochrome P450 3A4 (CYP3A4) appears to be the major isozyme responsible for loperamide metabolism, with minor contributions from CYP2B6 (9). At the doses used to control diarrhea, LOP has very poor penetration of the blood-brain barrier and produces no central opioid effects, such as respiratory depression, pupillary constrictions, analgesia, or changes in alertness (26). The poor central nervous system (CNS) penetration is attributed both to LOP active cellular efflux via the multidrug resistance transporter P-glycoprotein (P-gp) in the blood-brain barrier and to low systemic oral bioavailability (24). When P-gp is inhibited, LOP and its metabolites may potentially enter the brain and cause opioid-induced central neurological adverse events (AEs) (23, 24).Current treatment for human immunodeficiency virus type 1 (HIV-1) infection consists of a combination of antiretroviral agents of different classes. Tipranavir (TPV) is a potent nonpeptidic HIV-1 and HIV-...