Bisphosphonates: a review of their pharmacokinetic properties
Humans; Animals; Protein Binding; Dose-Response Relationship; Drug; Clodronate; Structure-Activity Relationship; Biological Availability; Blood Proteins/metabolism; Diphosphonates/pharmacokinetics/urine; Intestinal Absorption/physiology; Tissue Distribution/physiology
Bisphosphonates are a unique class of drugs. As a family, they are characterized pharmacologically by their ability to inhibit bone resorption, whereas, pharmacokinetically, they are classified by their similarity in absorption, distribution, and elimination. Although all bisphosphonates have similar physicochemical properties, their antiresorbing activities differ substantially. Activity is dramatically increased when the amino group is contained in the aliphatic carbon chain. For example, alendronate, an aminobisphosphonate, is approximately 700-fold more potent than etidronate, both in vitro and in vivo. In general, bisphosphonates are poorly absorbed from the gastrointestinal tract as a result of their poor lipophilicity. In vitro and in vivo studies have shown that bisphosphonates are absorbed from the gastrointestinal tract via paracellular transport. Systemically available bisphosphonates disappear very rapidly from plasma, and are partly taken up by the bone and partly excreted by the kidney. The relative contribution of these two processes to overall plasma elimination differs significantly among bisphosphonates. To date, all bisphosphonates studied show no evidence of metabolism. Renal excretion is the only route of elimination. Studies with alendronate in rats indicate that the drug is actively secreted by an uncharacterized renal transport system, and not by the anionic or cationic renal transport systems. Bisphosphonates bind preferentially to bones which have high turnover rates, and their distribution in bone is not homogeneous. After bone uptake, the bisphosphonates are liberated again only when the bone in which they are deposited is resorbed. Thus, the half-life of bisphosphonates in bone is very long, ranging among different species from 1 to 10 years, depending largely on the rate of bone turnover.
1996
Lin JH
Bone
1996
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1016/8756-3282(95)00445-9" target="_blank" rel="noreferrer">10.1016/8756-3282(95)00445-9</a>
Clinical use of methadone
Humans; Analgesics; Drug Interactions; Therapeutic Equivalency; Half-Life; Drug Administration Schedule; Pain/drug therapy; Receptors; Biological Availability; Opioid/adverse effects/pharmacokinetics/therapeutic use; Dosage Forms; Kidney Diseases/metabolism; Liver Diseases/metabolism; Methadone/adverse effects/pharmacokinetics/therapeutic use; Opioid-Related Disorders/drug therapy; Opioid/agonists; Substance Withdrawal Syndrome/etiology
Methadone hydrochloride is a mu-opioid agonist that has been used for the treatment of pain and for the management and maintenance of opioid withdrawal for over 50 years. Several characteristics make methadone a useful drug. However, these same characteristics and wide interpatient variability can make methadone difficult to use safely. A MEDLINE search was conducted on publications between January 1996 and May 2001 to identify literature relevant to this subject. Those publications were reviewed, and from them, other literature was identified and reviewed. Published studies demonstrate methadone's efficacy in pain management and in opioid withdrawal. However, interpatient variability in pharmacokinetic variables of methadone produces difficulties in developing guidelines for methadone use. Clinicians should not be deterred from use of this drug which has been shown to benefit patients in both pain management and methadone maintenance, but an individualized patient approach must be taken to use methadone safely.
2002
Layson-Wolf C; Goode JV; Small RE
Journal of Pain and Palliative Care Pharmacotherapy
2002
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1080/j354v16n01_04" target="_blank" rel="noreferrer">10.1080/j354v16n01_04</a>
Sublingual absorption of selected opioid analgesics
Humans; Adult; Analgesics; Time Factors; Analysis of Variance; Non-U.S. Gov't; P.H.S.; Research Support; U.S. Gov't; Comparative Study; Administration; Biological Availability; Buprenorphine/pharmacokinetics; Fentanyl/pharmacokinetics; Heroin/pharmacokinetics; Hydromorphone/pharmacokinetics; Levorphanol/pharmacokinetics; Methadone/pharmacokinetics; Morphine/blood/pharmacokinetics; Mouth/metabolism; Naloxone/pharmacokinetics; Opioid/administration & dosage/pharmacokinetics; Oxycodone/pharmacokinetics; Sublingual
Ongoing interest in the improvement of pain management with opioid analgesics had led to the investigation of sublingual opioid absorption. The present report determined the percent absorption of selected opioid analgesics from the oral cavity of normal subjects under conditions of controlled pH and swallowing when a 1.0 ml aliquot of the test drug was placed under the tongue for a 10-minute period. Compared with morphine sulfate at pH 6.5 (18% absorption), buprenorphine (55%), fentanyl (51%), and methadone (34%) were absorbed to a significantly greater extent (p less than 0.05), whereas levorphanol, hydromorphone, oxycodone, heroin, and the opioid antagonist naloxone were not. Overall, lipophilic drugs were better absorbed than were hydrophilic drugs. Plasma morphine concentration-time profiles indicate that the apparent sublingual bioavailability of morphine is only 9.0% +/- 11.9% (SD) of that after intramuscular administration. In the same subjects the estimated sublingual absorption was 22.4% +/- 9.2% (SD), indicating that the sublingual absorption method may overestimate apparent bioavailability. When the oral cavity was buffered to pH 8.5, methadone absorption was increased to 75%. Thus, an alkaline pH microenvironment that favors the unionized fraction of opioids increased sublingual drug absorption. Although absorption was found to be independent of drug concentration, it was contact time dependent for methadone and fentanyl but not for buprenorphine. These results indicate that although the sublingual absorption and apparent sublingual bioavailability of morphine are poor, the sublingual absorption of methadone, fentanyl, and buprenorphine under controlled conditions is relatively high.
1988
Weinberg DS; Inturrisi CE; Reidenberg B; Moulin DE; Nip TJ; Wallenstein S; Houde RW; Foley KM
Clinical Pharmacology And Therapeutics
1988
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1038/clpt.1988.159" target="_blank" rel="noreferrer">10.1038/clpt.1988.159</a>
The use of methadone for cancer pain
Child; Humans; Analgesics; Attitude of Health Personnel; Treatment Outcome; Information Dissemination; Patient Selection; Drug Interactions; Clinical Protocols; Drug Administration Schedule; Practice; Attitudes; Health Knowledge; Palliative Care/methods; Dose-Response Relationship; Drug; Neoplasms/complications; Pain/diagnosis/drug therapy/etiology; Biological Availability; Drug Costs; Drug Industry/economics; Drug Information Services; Metabolic Clearance Rate; Methadone/chemistry/economics/pharmacology/therapeutic use; Morphine/pharmacology/therapeutic use; Opioid/chemistry/economics/pharmacology/therapeutic use
Methadone is not a new analgesic drug [69]. Several studies have demonstrated that methadone is a valid alternative to morphine, hydromorphone, and fentanyl for the treatment of cancer-related pain, and extensive reviews on the subject have been published in recent years [10,23,25,64,70,71]. Most people involved in pain therapy, however, are not well informed about the properties of methadone. The authors believe that the low cost of methadone paradoxically contributes to the limited knowledge of its characteristics and to the restricted therapeutic use of this drug. The low cost of methadone means there is little financial incentive for pharmaceutical companies to invest in research or to disseminate scientific information. Unfortunately, the lack of scientific information from pharmaceutical companies frequently results in a lack of knowledge on the part of physicians. Unless the existing approach changes, both culturally and politically, ignorance about methadone will persist among medical experts. The low cost of methadone, rather than being an advantage, will result in the limited exploitation of an effective drug.
2002
Ripamonti C; Bianchi M
Hematology/oncology Clinics Of North America
2002
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1016/s0889-8588(02)00017-5" target="_blank" rel="noreferrer">10.1016/s0889-8588(02)00017-5</a>